Compounds and compositions for the treatment of parasitic diseases

ABSTRACT

The present invention provides compounds of formula I: 
                         
or a pharmaceutically acceptable salt, tautomer, or stereoisomer, thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating, preventing, inhibiting, ameliorating, or eradicating the pathology and/or symptomology of a disease caused by a  Plasmodium  parasite, such as malaria.

CROSS-REFERENCED TO RELATED APPLICATIONS

This application claims the benefit of priority to PCT ApplicationNumber PCT/US2013/070601, filed on 18 Nov. 2013 and claiming priority toU.S. Provisional Patent Application No. 61/728,018, filed 19 Nov. 2012and U.S. Provisional Application No. 61/847,860 filed 18 Jul. 2013. Thefull disclosures of these applications are incorporated herein byreference in its entirety and for all purposes.

BACKGROUND OF THE INVENTION

Field of the Invention

The invention provides a class of compounds, pharmaceutical compositionscomprising such compounds and methods of using such compounds to treator prevent malaria.

Background

Malaria is an infectious disease caused by four protozoan parasites:Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; andPlasmodium malaria. These four parasites are typically transmitted bythe bite of an infected female Anopheles mosquito. Malaria is a problemin many parts of the world and over the last few decades the malariaburden has steadily increased. An estimated 1-3 million people die everyyear from malaria—mostly children under the age of 5. This increase inmalaria mortality is due in part to the fact that Plasmodium falciparum,the deadliest malaria parasite, has acquired resistance against nearlyall available antimalarial drugs, with the exception of the artemisininderivatives. Further for true causal prophylaxis and interrupttransmission of the disease, prevention of liver stage development iscrucial, because development of the proceeding infectious blood stagegametocytes would be block. A single drug effective againsthepatichypnozoites, primaquine, is available, but its deployment iscurtailed by its potential side effects.

Leishmaniasis is caused by one or more than 20 varieties of parasiticprotozoa that belong to the genus Leishmania, and is transmitted by thebite of female sand flies. Leishmaniasis is endemic in about 88countries, including many tropical and sub-tropical areas.

There are four main forms of Leishmaniasis. Visceral leishmaniasis, alsocalled kala-azar, is the most serious form and is caused by the parasiteLeishmania donovani. Patients who develop visceral leishmaniasis can diewithin months unless they receive treatment. The two main therapies forvisceral leishmaniasis are the antimony derivatives sodiumstibogluconate (Pentostam®) and meglumine antimoniate (Glucantim®).Sodium stibogluconate has been used for about 70 years and resistance tothis drug is a growing problem. In addition, the treatment is relativelylong and painful, and can cause undesirable side effects.

Human African Trypanosomiasis, also known as sleeping sickness, is avector-borne parasitic disease. The parasites concerned are protozoabelonging to the Trypanosoma Genus. They are transmitted to humans bytsetse fly (Glossina Genus) bites which have acquired their infectionfrom human beings or from animals harboring the human pathogenicparasites.

Chagas disease (also called American Trypanosomiasis) is another humanparasitic disease that is endemic amongst poor populations on theAmerican continent. The disease is caused by the protozoan parasiteTrypanosoma cruzi, which is transmitted to humans by blood-suckinginsects. The human disease occurs in two stages: the acute stage, whichoccurs shortly after infection and the chronic stage, which can developover many years. Chronic infections result in various neurologicaldisorders, including dementia, damage to the heart muscle and sometimesdilation of the digestive tract, as well as weight loss. Untreated, thechronic disease is often fatal.

The drugs currently available for treating Chagas disease are Nifurtimoxand benzindazole. However, problems with these current therapies includetheir diverse side effects, the length of treatment, and the requirementfor medical supervision during treatment. Furthermore, treatment isreally only effective when given during the acute stage of the disease.Resistance to the two frontline drugs has already occurred. Theantifungal agent Amphotericin b has been proposed as a second-line drug,but this drug is costly and relatively toxic.

In view of the foregoing, it is desirable to develop novel compounds asantiparasitic agents.

SUMMARY OF THE INVENTION

The invention therefore provides a compound of the formula (I):

or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof,wherein

-   -   n is 0, 1, 2 or 3;    -   p is 0, 1, 2 or 3;    -   L is selected from the group consisting of *—(CHR₃)₁₋₃—,        *—CHR₃N(R₂)—, *—CHR₃O—, *—CHR₃S—, *—CHR₃S(O)—, *—CHR₃N(R₂)CHR₃—,        *—C(O)—, *—C(O)N(R₂)—, *—C(O)N(R₂)CHR₃—, *—N(R₂)—, *—N(R₂)CHR₃—,        *—N(R₂)C(O)—, *—N(R₂)C(O)N(R₂)—, *—N(R₂)S(O)₂—, wherein        -   * represents the point of attachment of L to the            pyrazolo[1,5-a]pyridine fused ring depicted in Formula I;        -   each R₂ is independently selected from the group consisting            of hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, R—C₀₋₄alkylene, and            R—C₀₋₄alkylene-C(O)—, wherein R is selected from the group            consisting of hydroxyl, C₁₋₄alkoxy, amino, C₁₋₄alkylamino,            C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, and C₅₋₆heteroaryl,            wherein the C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, and            C₅₋₆heteroaryl of R are each unsubstituted or substituted            with 1-2 substituents independently selected from the group            consisting of halo, amino, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxy,            oxo, and C₅₋₆heteroaryl; and        -   each R₃ is independently selected from the group consistin            of hydrogen and C₁₋₄alkyl;    -   Ring A is selected from the group consistin of C₆₋₁₀aryl and        C₃₋₁₀heteroaryl;    -   Ring C is selected from the group consisting of C₈₋₁₀aryl,        C₅₋₁₀heteroaryl, C₅₋₇cycloalkyl, C₅₋₇heterocycloalkyl, and a        fused bicyclyl comprising a C₅₋₆heterocycloalky fused to a        phenyl;    -   each R₁ is independently selected from the group consisting of        halo, cyano, amino, C₁₋₄alkyl, C₁₋₄alkoxyl, halo-C₁₋₄alkyl,        —C(O)NR₇R₈, —NHC(O)R₁₁, phenyl, and C₅₋₆heteroaryl; wherein        -   the phenyl and C₅₋₆heteroaryl of R₁ are each unsubstituted            or substituted with 1-2 substituents independently selected            from the group consisting of C₁₋₄alkyl, amino, halo, and            C₁₋₄alkylamino;        -   R₇ and R₈ are each independently selected from the group            consisting of hydrogen, C₁₋₄alkyl or haloC₁₋₄alkyl;        -   R₁₁ is C₁₋₆alkyl unsubstituted or substituted with 1-2            substituents independently selected from the group            consisting of amino, C₃₋₆cycloalkyl and            C₄₋₆heterocycloalkyl;    -   R₁₇ is selected from the group consisting of cyano, halo,        C₁₋₄alkyl, halo-C₁₋₄alkyl, oxo, C₃₋₆cycloalkyl, and        —SO₂—C₁₋₄alkyl.

In a second aspect, the present invention provides a pharmaceuticalcomposition which contains a compound selected from Formula I, IA, or aN-oxide derivative, individual isomers and mixture of isomers thereof;or a pharmaceutically acceptable salt thereof, in admixture with one ormore suitable excipients.

In a third aspect, the present invention provides a method of treating adisease in an animal in which a compound of the invention can prevent,inhibit, ameliorate, or eradicate the pathology and/or symptomology ofdisease caused by a parasite (such as, for example, Plasmodiumfalciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria,Trypanosoma cruzi or a parasite of the Leishmania genus such as, forexample, Leishmania donovani) which method comprises administering tothe animal a therapeutically effective amount of a compound selectedfrom Formula I, IA, or a N-oxide derivative, individual isomers andmixture of isomers thereof, or a pharmaceutically acceptable saltthereof.

In a fourth aspect, the present invention provides a compound fortreating, preventing, inhibiting, ameliorating, or eradicating thepathology and/or symptomology of a disease caused by a parasite (suchas, for example, Plasmodium falciparum, Plasmodium vivax, Plasmodiumovale, Plasmodium malaria, Trypanosoma cruzi or a parasite of theLeishmania genus such as, for example, Leishmania donovani).Particularly, the parasite is a Plasmodium which can be at the bloodstages or at the hepatic stages, and the disease is malaria.

In a fifth aspect, the present invention provides the use of a compoundselected from Formula I or Formula 1a in the manufacture of a medicamentfor treating a disease caused by a parasite in an animal. The diseasemay be malaria, leishmaniasis and/or Chagas disease.

In a sixth aspect, the present invention provides a process forpreparing compounds selected from Formula I, Formula 1a and the N-oxidederivatives, prodrug derivatives, individual isomers and mixture ofisomers thereof, and the pharmaceutically acceptable salts thereof.

Unless specified otherwise, the term “compounds of the presentinvention” refers to compounds of Fomula (I) and subformulae thereof,salts of the compound, hydrates or solvates of the compounds, salts, aswell as all stereoisomers (including diastereoisomers and enantiomers),tautomers and isotopically labeled compounds (including deuteriumsubstitutions). Compounds of the present invention further comprisepolymorphs of compounds of formula I (or subformulae thereof) and saltsthereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

“Acyl” as used herein refers to the radical —C(═O)R_(a), where R_(a) ishydrogen or a non-hydrogen substituent on the carbonyl carbon, formingdifferent carbonyl-containing groups including, but are not limited to,acids, acid halides, aldehydes, amides, esters, and ketones.

“Alkoxy” as used herein refers the radical —O-alkyl, wherein the alkylis as defined herein. C_(X)alkoxy and C_(X-Y)alkoxy as used hereindescribe alkoxy groups where X and Y indicate the number of carbon atomsin the alkyl chain. Representative examples of C₁₋₁₀alkoxy include, butare not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and decyloxy. Thealkyl portion of the alkoxy may be optionally substituted, and thesubstituents include those described for the alkyl group below.

“Alkyl” as used herein refers to a fully saturated branched orunbranched hydrocarbon chain having up to 10 carbon atoms. C_(X) alkyland C_(X-Y) alkyl as used herein describe alkyl groups where X and Yindicate the number of carbon atoms in the alkyl chain. For example,C₁₋₁₀ alkyl refers to an alkyl radical as defined above containing oneto ten carbon atoms. C₁₋₁₀ alkyl includes, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl and the like. Alkyl represented along with another radical likearylalkyl, heteroarylalkyl, alkoxyalkyl, alkoxyalkyl, alkylamino, wherethe alkyl portion shall have the same meaning as described for alkyl andis bonded to the other radical. For example, (C₆₋₁₀)aryl(C₁₋₃)alkylincludes, benzyl, phenylethyl, 1-phenylethyl, 3-phenylpropyl,2-thienylmethyl, 2-pyridinylmethyl and the like.

Unless stated otherwise specifically in the specification, an alkylgroup may be unsubstituted or substituted by one or more substituents tothe extent that such substitution makes sense chemically. Typicalsubstituents include, but are not limited to halo, hydroxyl, alkoxy,cyano, amino, acyl, aryl, arylalkyl, and cycloalkyl, or an heteroformsof one of these groups, and each of which can be substituted by thesubstituents that are appropriate for the particular group.

“Alkenyl” as used herein refers to a straight or branched, hydrocarbonchain having up to 10 carbon atoms and at least one carbon-carbon doublebond. C_(X)alkenyl and C_(X-Y)alkenyl as used herein describe alkenylgroups where X and Y indicate the number of carbon atoms in the alkenylchain. Examples of C₂₋₇alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like. The alkenyl may be optionally substituted, and thesubstituents include those described for the alkyl group descriedherein.

“Alkynyl” as used herein refers to a straight or branched, hydrocarbonchain having up to 10 carbon atoms and at least one carbon-carbon triplebond. C_(X)alkenyl and C_(X-Y)alkenyl as used herein describe alkynylgroups, where X and Y indicate the number of carbon atoms in the alkynylchain. For example, C₂₋₇alkenyl include, but are not limited to,ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. Analkynyl may be optionally substituted, and the substituents includethose described for the alkyl group described herein.

“Alkylene” as used herein refers to a divalent alkyl group definedherein. Examples of C₁₋₁₀alkylene includes, but are not limited to,methylene, ethylene, n-propylene, iso-propylene, n-butylene,sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene,neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene,2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene andn-decylene. An alkylene group may be optionally substituted, and thesubstituents include those described for the alkyl group describedherein.

“Alkenylene” as used herein refers to a divalent alkenyl group definedherein. Examples of C₁₋₃alkenylene include, but are not limited to,ethene-1,2-diyl, propene-1,3-diyl, and methylene-1,1-diyl. An alkenylenemay be optionally substituted, and the substituents include thosedescribed for the alkyl group described herein.

“Alkynylene” as used herein refers to a divalent alkynyl group definedherein. Examples of alkynylene include ethyne-1,2-diylene,propyne-1,3-diylene, and the like. An alkynylene may be optionallysubstituted, and the substituents include those described for the alkylgroup described herein.

“Amino” as used herein refers to the radical —NH₂. When an amino isdescribed as “substituted” or “optionally substituted”, the termincludes NR′R″ wherein each R′ and R″ is independently H, or is analkyl, alkenyl, alkynyl, acyl, aryl, aryl, cycloalkyl, arylalkylcycloalkylalkyl group or a heteroform of one of these groups, and eachof the alkyl, alkenyl, alkynyl, acyl, aryl, arylalkyl or groups orheteroforms of one of these groups, each of which is optionallysubstituted with the substituents described herein as suitable for thecorresponding group.

The term “amino” also includes forms wherein R′ and R″ are linkedtogether to form a 3-8 membered ring which may be saturated, unsaturatedor aromatic and which contains 1-3 heteroatoms independently selectedfrom N, O and S as ring members, and which is optionally substitutedwith the substituents described as suitable for alkyl groups or, ifNR′R″ is an aromatic group, it is optionally substituted with thesubstituents described as typical for heteroaryl groups.

Unless indicated otherwise, the compounds of the invention containingamino moieties may include protected derivatives thereof. Suitableprotecting groups for amino moieties include acetyl,tert-butoxycarbonyl, benzyloxycarbonyl, and the like.

“Alkylamino” as used herein refers to the radical —NR_(a)R_(b), where atleast one of, or both, R_(a) and R_(b) are an alkyl group as describedherein. An C₁₋₄alkylamino group includes —NHC₁₋₄alkyl and—N(C₁₋₄alkyl)₂; e.g., —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃), —N(CH₂CH₃)₂, andthe like.

“Aromatic” as used herein refers to a moiety wherein the constituentatoms make up an unsaturated ring system, where all atoms in the ringsystem are sp² hybridized and the total number of pi electrons is equalto 4n+2. An aromatic ring may be such that the ring atoms are onlycarbon atoms or may include carbon and non-carbon atoms (seeHeteroaryl).

“Aryl” as used herein refers to a 6-14 membered monocyclic or polycyclicaromatic ring assembly where all the ring atoms are carbon atoms.Typically, the aryl is a 6 membered monocyclic, a 10-12 memberedbicyclic or a 14-membered fused tricyclic aromatic ring system.C_(X)aryl and C_(X-Y)aryl as used herein describe an aryl group where Xand Y indicate the number of carbon atoms in the ring system. C₆₋₁₄arylsinclude, but are not limited to, phenyl, biphenyl, naphthyl, azulenyl,and anthracenyl.

An aryl may be unsubstituted or substituted by 1-5 (such as one, or two,or three) substituents independently selected from the group consistingof hydroxy, thiol, cyano, nitro, C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkynyl,C₁₋₄alkoxy, thioC₁₋₄alkyl, C₁₋₄alkenyloxy, C₁₋₄alkynyloxy, halogen,C₁₋₄alkylcarbonyl, carboxy, C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino,di-C₁₋₄alkylamino, C₁₋₄alkylaminocarbonyl, di-C₁₋₄alkylaminocarbonyl,C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl,sulfamoyl, alkylsulfamoyl, C₁₋₄alkylaminosulfonyl, aryl, heteroaryl,cycloalkyl and heterocycloalkyl, wherein each of the afore-mentionedsubstitutents may be further substituted by one or more substituentsindependently selected from halogen, alkyl, hydroxyl or C₁₋₄alkoxygroups.

When an “aryl” is represented along with another radical like“arylalkyl”, “aryloxyalkyl”, “aryloxycarbonyl”, “aryloxy-carbonylalkyl”,the aryl portion shall have the same meaning as described in theabove-mentioned definition of “aryl”.

“Aryloxy” as used herein, refers to the radical —O-aryl, wherein aryl isas defined herein.

“Bicyclic” or “bicyclyl” as used here in refers to a ring assembly oftwo rings where the two rings are fused together, linked by a singlebond or linked by two bridging atoms. The rings may be a carbocyclyl, aheterocyclyl, or a mixture thereof.

“Bridging ring” as used herein refers to a polycyclic ring system wheretwo ring atoms that are common to two rings are not directly bound toeach other. One or more rings of the ring system may also compriseheteroatoms as ring atoms. Non-exclusive examples of bridging ringsinclude norbornanyl, 7-oxabicyclo[2.2.1]heptanyl, adamantanyl, and thelike.

“Carbamoyl” as used herein refers to the radical —C(O)NR_(a)— whereR_(a) is H, or is an alkyl, alkenyl, alkynyl, acyl, aryl, or arylalkylgroup or a heteroform of one of these groups, and each of the alkyl,alkenyl, alkynyl, acyl, aryl, arylalkyl or heteroforms of one of thesegroups is optionally substituted with the substituents described hereinas suitable for the corresponding group.

“Cycloalkyl”, as used herein, means a radical comprising a non-aromatic,saturated or partially unsaturated, monocyclic, bicyclic, tricyclic,fused, bridged or spiro polycyclic hydrocarbon ring system of 3-20carbon atoms. C_(X)cycloalkyl and C_(X-Y)cycloalkyl are typically usedwhere X and Y indicate the number of carbon atoms in the ring assembly.For example, C₃₋₆cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl.

Exemplary monocyclic cycloalkyl include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

Exemplary bicyclic cycloalkyls include bornyl, norbornanyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl. Exemplary tricyclic cycloalkyl groups include, forexample, adamantyl.

A cycloalkyl may be unsubstituted or substituted by one, or two, orthree, or more substituents independently selected from the groupconsisting of hydroxyl, thiol, cyano, nitro, oxo, alkylimino, C₁₋₄alkyl,C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄thioalkyl, C₁₋₄alkenyloxy,C₁₋₄alkynyloxy, halogen, C₁₋₄alkylcarbonyl, carboxy, C₁₋₄alkoxycarbonyl,amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino, C₁₋₄alkylaminocarbonyl,di-C₁₋₄alkylaminocarbonyl, C₁₋₄alkylcarbonylamino,C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl,C₁₋₄alkylaminosulfonyl where each of the afore-mentioned hydrocarbongroups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be furthersubstituted by one or more residues independently selected at eachoccurrence from halogen, hydroxyl or C₁₋₄alkoxy groups.

“Cycloalkylene”, as used herein, refers to a divalent radical comprisinga cycloalkyl ring assembly as defined herein.

“Cycloalkoxy”, as used herein, refers to —O-cycloalkyl, wherein thecycloalkyl is defined herein. Representative examples ofC_(3.12)cycloalklyoxy include, but are not limited to, monocyclic groupssuch as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclopentenyloxy,cyclohexyloxy and cyclohexenyloxy and the like. Exemplary bicyclichydrocarbon groups include bornyloxy, indyloxy, hexahydroindyloxy,tetrahydronaphthyloxy, decahydronaphthyloxy, bicyclo[2.1.1]hexyloxy,bicyclo[2.2.1]heptyloxy, bicyclo[2.2.1]heptenyloxy,6,6-dimethylbicyclo[3.1.1]heptyloxy,2,6,6-trimethylbicyclo[3.1.1]heptyloxy, bicyclo[2.2.2]octyloxy and thelike. Exemplary tricyclic hydrocarbon groups include, for example,adamantyloxy.

“Cyano”, as used herein, refers to the radical —CN.

“EC₅₀”, refers to the molar concentration of an inhibitor or modulatorthat produces 50% efficacy.

“Fused ring”, as used herein, refers to a multi-ring assembly whereinthe rings comprising the ring assembly are so linked that the ring atomsthat are common to two rings are directly bound to each other. The fusedring assemblies may be saturated, partially saturated, aromatics,carbocyclics, heterocyclics, and the like. Non-exclusive examples ofcommon fused rings include decalin, naphthalene, anthracene,phenanthrene, indole, benzofuran, purine, quinoline, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo.

“Haloalkyl”, or halo-substituted-alkyl” as used herein, refers to analkyl as defined herein, which is substituted by one or more halo atomsdefined herein. The haloalkyl can be mono-haloalkyl, dihaloalkyl orpolyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo,bromo, chloro or fluoro within the alkyl group. Dihaloalky andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups within the alkyl. C_(X)haloalkyland C_(X-Y)haloalkyl are typically used where X and Y indicate thenumber of carbon atoms in the alkyl chain. Non-limiting examples ofC₁₋₄haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. AC₁₋₄perhaloalkyl group refers to a C₁₋₄alkyl group having all hydrogenatoms replaced with halo atoms.

“Heteroaryl”, as used herein, refers to a 5-14 membered ring assembly(e.g., a 5-7 membered monocycle, an 8-10 membered bicycle, or a 13-14membered tricyclic ring system) having 1 to 8 heteroatoms selected fromN, O and S as ring atoms and the remaining ring atoms are carbon atoms.The nitrogen atoms of such heteroaryl rings can be optionallyquaternerized and the sulfur atoms of such heteroaryl rings can beoptionally oxidized. C_(X)heteroaryl and C_(X-Y)heteroaryl as usedherein describe heteroaryls where X and Y indicate the number of ringatoms in the heteroaryl ring. Typical C₅₋₇heteroaryl groups includethienyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyrrolinyl,thiazolyl, 1,3,4-thiadiazolyl, isothiazolyl, oxazolyl, oxadiazoleisoxazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl,pyrazinyl, pyrimidinyl, and the like. Bicyclic or tricyclicC₈₋₁₄heteroaryls include, but are not limited to, those derived frombenzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine,quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine,thieno[2,3-b]pyridine, quinazolinyle, pteridinyl, indolizine,imidazo[1,2a]pyridine, quinoline, quinolinyl, isoquinoline, phthalazine,quinoxaline, naphthyridine, naphthyridinyl, quinolizine, indolyl,indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole,benzothiazole, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,purinyl, carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone.

A heteroaryl may be unsubstituted or substituted with one or moresubstituents independently selected from hydroxyl, thiol, cyano, nitro,C₁₋₄alkyl, C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy, thioC₁₋₄alkyl,C₁₋₄alkenyloxy, C₁₋₄alkynyloxy, halogen, C₁₋₄alkylcarbonyl, carboxy,C₁₋₄alkoxycarbonyl, amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino,C₁₋₄alkylaminocarbonyl, di-C₁₋₄alkylaminocarbonyl,C₁₋₄alkylcarbonylamino, C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl,sulfamoyl, alkylsulfamoyl, C₁₋₄alkylaminosulfonyl where each of theafore-mentioned hydrocarbon groups (e.g., alkyl, alkenyl, alkynyl,alkoxy residues) may be further substituted by one or more residuesindependently selected at each occurrence from halogen, hydroxyl orC₁₋₄alkoxy groups.

When a heteroaryl is represented along with another radical like“heteroaryloxy”, “heteroaryloxyalkyl”, “heteroaryloxycarbonyl”, theheteroaryl portion shall have the same meaning as described in theabove-mentioned definition of “heteroaryl”.

“Heteroaryloxy”, as used herein, refers to an —O-heteroaryl group,wherein the heteroaryl is as defined in this Application.

“Heteroatom”, as used herein, refers to an atom that is not a carbonatom. Particular examples of heteroatoms include, but are not limited tonitrogen, oxygen, and sulfur.

“Heterocycloalkyl”, as used herein, refers to a 4-20 membered,non-aromatic, saturated or partially unsaturated, monocyclic orpolycyclic ring system, comprising 1-8 heteroatoms as ring atoms andthat the remaining ring atoms are carbon atoms. The heteroatoms areselected from N, O, and S, preferably O and N. The nitrogen atoms of theheterocycloalkyl can be optionally quaternerized and the sulfur atoms ofthe heterocycloalkyl can be optionally oxidized. The heterocycloalkylcan include fused or bridged rings as well as spirocyclic rings.C_(X)heterocycloalkyl and C_(X-Y)heterocycloalkyl are typically usedwhere X and Y indicate the number of ring atoms in the ring. Typically,the heterocycloalkyl is 4-8-membered monocyclic ring containing 1 to 3heteroatoms, a 7 to 12-membered bicyclic ring system containing 1-5heteroatoms, or a 10-15-membered tricyclic ring system containing 1 to 7heteroatoms. Examples of C₄₋₆heterocycloalkyl include azetidinyl,tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine,1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine,imidazoline, pyrazolidinyl, pyrroline, pyrrolidine, tetrahydropyran,dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane,oxathiane, thiomorpholine, and the like

A heterocycloalkyl may be unsubstituted or substituted with 1-5substituents (such as one, or two, or three) each independently selectedfrom hydroxyl, thiol, cyano, nitro, oxo, alkylimino, C₁₋₄alkyl,C₁₋₄alkenyl, C₁₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄thioalkyl, C₁₋₄alkenyloxy,C₁₋₄alkynyloxy, halogen, C₁₋₄alkylcarbonyl, carboxy, C₁₋₄alkoxycarbonyl,amino, C₁₋₄alkylamino, di-C₁₋₄alkylamino, C₁₋₄alkylaminocarbonyl,di-C₁₋₄alkylaminocarbonyl, C₁₋₄alkylcarbonylamino,C₁₋₄alkylcarbonyl(C₁₋₄alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl,C₁₋₄alkylaminosulfonyl where each of the afore-mentioned hydrocarbongroups (e.g., alkyl, alkenyl, alkynyl, alkoxy residues) may be furthersubstituted by one or more residues independently selected at eachoccurrence from halogen, hydroxyl or C₁₋₄alkoxy groups.

When a heterocycloalkyl forms part of other groups like“heterocycloalkyl-alkyl”, “heterocycloalkoxy”, “heterocycloalkyl-aryl”,the heteroaryl portion shall have the same meaning as described in theabove-mentioned definition of “heteroaryl”

“Heterocycloalkylene”, as used herein, refers to a cycloalkylene, asdefined in this Application, provided that one or more of the ringmember carbon atoms is replaced by a heteroatom.

“Heterocycloalkyl fused to a phenyl” as used herein, refers to abicyclic fused ring system that one of the ring is heterocycloalkyl asdefined above and the other ring is a phenyl. A heterocycloalkyl fusedto a phenyl includes but are not limited to benzo[b][1,4]oxazinyl,oxo-benzo[b][1,4]oxazinyl, tetrahydroquinoxalinyl, tetrahydroquinolinyl,indolinyl, benzo[d]imidazolyl, and the like.

“Heterocyclyl”, “heterocycle” or “heterocyclo”, as used herein, refersto a 3-20 membered, monocyclic or polycyclic ring system containing atleast one heteroatom moiety selected from the group consisting of N, O,SO, SO₂, (C═O), and S, and preferably N, O, S, optionally containing oneto four additional heteroatoms in each ring. C_(X)heterocyclyl andC_(X-Y)heterocyclyl are typically used where X and Y indicate the numberof ring atoms in the ring system. Unless otherwise specified, aheterocyclyl may be saturated, partially unsaturated, aromatic orpartially aromatic.

Hydroxy, as used herein, refers to the radical —OH.

“Hydroxyalkyl” or “hydroxyl-substituted alkyl” as used herein, refers toan alkyl as defined herein, having one or more of the available hydrogenof the alkyl replaced by a hydroxyl group. For example, ahydroxyC₁₋₄alkyl includes, but are not limited to, —CH₂CH₂OH,—CH(OH)CH₂CH₂OH, —CH(OH)CH₂CH(OH)CH₃.

“Nitro”, as used herein, refers to the radical —NO₂.

“Oxo”, as used herein, refers to the divalent radical ═O

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. Examples of protected group includes, butare not limited to, acetyl, tetrahydropyran, methoxymethyl ether,β-methoxyethoxymethyl ether, p-methoxybenzyl, methylthiomethyl ether,pivaloyl, silyl ether, carbobenzyloxy, benzyl, tert-butoxycarbonyl,p-methoxyphenyl, 9-fluorenylmethyloxycarbonyl, acetals, ketals, acylals,dithianes, methylesters, benzyl esters, tert-butyl esters, and silylesters. A comprehensive list of suitable protecting groups can be foundin T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, Inc. 1999.

“Unsubstituted or substituted” or “optionally substituted” as usedherein indicate the substituent bound on the available valance of anamed group or radical. “Unsubstituted” as used herein indicates thatthe named group or radical will have no further non-hydrogensubstituents. “Substituted” or “optionally substituted” as used hereinindicates that at least one of the available hydrogen atoms of namedgroup or radical has been (or may be) replaced by a non-hydrogensubstituent.

“Substituted terminally” as used herein referred to a substituentreplacing a hydrogen at a terminal position of the parent molecule. Forexample C₁₋₄alkyl substituted terminally by an amino means—C₁₋₄alkylene-amino, which includes —(CH₂)—NH₂, —(CH₂)₂—NH₂,—(CH₂)₃—NH₂, —(CH₂)CH₂(CH₂—NH₂), —(CH₂)₄—NH₂,—C(CH₂)(CH₂CH₂—NH₂)—C(CH₃)₂(CH₂—NH₂), and the like.

Unless otherwise specified, examples of substituents may include, butare not limited to, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,C₁₋₆alkoxy, C₆₋₁₀aryloxy, heteroC₅₋₁₀aryloxy, carbonyl, oxycarbonyl,aminocarbonyl, amino, C₁₋₆alkylamino, sulfonamido, imino, sulfonyl,sulfinyl, C₁₋₆alkyl, C₁₋₆haloalkyl, hydroxyC₁₋₆alkyl, carbonylC₁₋₆alkyl,thiocarbonylC₁₋₁₀alkyl, sulfonylC₁₋₆alkyl, sulfinylC₁₋₆alkyl,C₁₋₁₀azaalkyl, iminoC₁₋₆alkyl, C₃₋₁₂cycloalkylC₁₋₆alkyl,C₄₋₁₅heterocycloalkylC₁₋₆alkyl, C₆₋₁₀arylC₁₋₆alkyl,C₅₋₁₀heteroarylC₁₋₆alkyl, C₁₀₋₁₂bicycloarylC₁₋₆alkyl,C₉₋₁₂heterobicycloarylC₁₋₆alkyl, C₃₋₁₂cycloalkyl, C₄₋₁₂heterocycloalkyl,C₉₋₁₂bicycloalkyl, C₃₋₁₂heterobicycloalkyl, C₄₋₁₂aryl, heteroC₁₋₁₀aryl,C₉₋₁₂bicycloaryl and C₄₋₁₂heterobicycloaryl.

“Sulfamoyl” as used herein refers to the radical —S(O)₂NR_(a)R_(b) whereR_(a) and R_(b) are independently H, or is an alkyl, alkenyl, alkynyl,acyl, aryl, aryl, cycloalkyl, arylalkyl cycloalkylalkyl group or aheteroform of one of these groups, and each of the alkyl, alkenyl,alkynyl, acyl, aryl, arylalkyl groups or heteroforms of one of thesegroups, is optionally substituted with the substituents described hereinas suitable for the corresponding group.

“Sulfanyl” as used herein, means the radical —S—.

“Sulfinyl”, as used herein, means the radical —S(O)—. It is noted thatthe term “sulfinyl” when referring to a monovalent substituent canalternatively refer to a substituted sulfinyl group, —S(═O)R, where R ishydrogen or a non-hydrogen substituent on the sulfur atom formingdifferent sulfinyl groups including sulfinic acids, sulfinamides,sulfinyl esters, and sulfoxides.

“Sulfonyl”, as used herein, means the radical —S(O)₂—. It is noted thatthe term “sulfonyl” when referring to a monovalent substituent canalternatively refer to a substituted sulfonyl group, —S(═O)₂R, where Ris hydrogen or a non-hydrogen substituent on the sulfur atom formingdifferent sulfonyl groups including sulfonic acids, sulfonamides,sulfonate esters, and sulfones.

“Thiocarbonyl”, as used herein, refers to the radical —C(═S)—. It isnoted that the term thiocarbonyl when referring to a monovalentsubstituent can alternatively refer to a substituted thiocarbonyl group,—C(═S)R, where R is hydrogen or a non-hydrogen substituent on the carbonatom forming different thiocarbonyl groups including thioacids,thioamides, thioesters, and thioketones.

are symbols denoting the point of attachment of X, to other part of themolecule.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkoxyalkyl wouldrepresent an alkoxy group attached to the parent molecule through analkyl group.

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, aC₁alkyl indicates that there is one carbon atom but does not indicatewhat are the substituents on the carbon atom. Hence, a C₁alkyl comprisesmethyl (i.e., —CH₃) as well as —CR_(a)R_(b)R_(c) where R_(a), R_(b), andR_(c) may each independently be hydrogen or any other substituent wherethe atom attached to the carbon is not a hydrogen atom. Hence, —CF₃,—CH₂OH and —CH₂CN, for example, are all C₁alkyls.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkoxyalkyl wouldrepresent an alkoxy group attached to the parent molecule through analkyl group.

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, aC₁alkyl indicates that there is one carbon atom but does not indicatewhat are the substituents on the carbon atom. Hence, a C₁alkyl comprisesmethyl (i.e., —CH₃) as well as —CR_(a)R_(b)R_(c) where R_(a), R_(b), andR_(c) may each independently be hydrogen or any other substituent wherethe atom attached to the carbon is not a hydrogen atom. Hence, —CF₃,—CH₂OH and —CH₂CN, for example, are all C₁alkyls.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides a novel class of compounds, pharmaceuticalcompositions comprising such compounds and methods of using suchcompounds to treat or prevent diseases or disorders associated with aparasite. In particular, the compounds can be used to treat malaria,leishmaniasis and/or Chagas disease. The compounds of the invention areeffective in inhibiting, ameliorating, or eradicating the pathologyand/or symptomology of the parasite at both the blood stage and hepaticstage.

In one embodiment, the compounds of the invention are of Formula I:

or a pharmaceutical acceptable salt, enantiomer or tautomer orstereoisomer thereof, wherein

-   -   n is 0, 1, 2 or 3;    -   p is 0, 1, 2 or 3;    -   L is selected from the group consisting of *—(CHR₃)₁₋₃—,        *—CHR₃N(R₂)—, *—CHR₃O—, *—CHR₃S—, *—CHR₃S(O)₂—, *—S(O)₂N(R₂)—,        *—CHR₃N(R₂)CHR₃—, *—C(O)—, *—C(O)N(R₂)—, *—C(O)N(R₂)CHR₃—,        *—N(R₂)—, *—N(R₂)CHR₃—, *—N(R₂)C(O)—, *—N(R₂)C(O)N(R₂)—,        *—N(R₂)S(O)₂—, wherein        -   * represents the point of attachment of L to the            pyrazolo[1,5-a]pyridine fused ring depicted in Formula I;        -   each R₂ is independently selected from the group consisting            of hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, R—C₀₋₄alkylene, and            R—C₀₋₄alkylene-C(O)—, wherein R is selected from the group            consisting of hydroxyl, C₁₋₄alkoxy, amino, C₁₋₄alkylamino,            C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, and C₅₋₆heteroaryl,            wherein the C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, and            C₅₋₆heteroaryl of R are each unsubstituted or substituted            with 1-2 substituents independently selected from the group            consisting of halo, amino, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxy,            oxo, and C₅₋₆heteroaryl; and.        -   each R₃ is independently selected from the group consisting            of hydrogen and C₁₋₄alkyl,    -   Ring A is selected from the group consisting of C₆₋₁₀aryl and        C₃₋₁₀heteroaryl;    -   Ring C is selected from the group consisting of C₆₋₁₀aryl,        C₅₋₁₀heteroaryl, C₅₋₇cycloalkyl, C₅₋₇heterocycloalkyl, and a        fused bicyclyl comprising a C₅₋₆heterocycloalky fused to a        phenyl;    -   each R₁ is independently selected from the group consisting of        halo, cyano, amino, C₁₋₄alkyl, C₁₋₄alkoxyl, halo-C₁₋₄alkyl,        C₁₋₄alkylsulfonyl, —C(O)OR₇, —NR₇R₈, —S(O)₂NR₇R₈, —C(O)NR₇R₈,        —NHC(O)R₁₁, phenyl, and C₅₋₆heteroaryl; wherein        -   the phenyl and C₅₋₆heteroaryl of R₁ are each unsubstituted            or substituted with 1-2 substituents independently selected            from the group consisting of C₁₋₄alkyl, amino, halo, and            C₁₋₄alkylamino;        -   R₇ and R₈ are each independently selected from the group            consisting of hydrogen, C₁₋₄alkyl, aminoC₁₋₄alkyl,            C₁₋₄alkylaminoC₁₋₄alkyl, hydroxyC₁₋₄alkyl,            C₁₋₄alkylsulfonyl, heteroC₄₋₆cycloalkyl, C₃₋₆cycloalkyl, and            haloC₁₋₄alkyl;        -   R₁₁ is C₁₋₆alkyl unsubstituted or substituted with 1-2            substituents independently selected from the group            consisting of amino, C₃₋₆cycloalkyl and            C₄₋₆heterocycloalkyl;    -   R₁₇ is selected from the group consisting of cyano, halo,        C₁₋₄alkyl, halo-C₁₋₄alkyl, oxo, C₃₋₆cycloalkyl, C₁₋₄alkoxy,        aminoC₁₋₄alkoxy, hydroxyC₁₋₄alkoxy, —C(O)OH, —C(O)NH₂, and        —SO₂—C₁₋₄alkyl.

In one embodiment of the compounds of the invention, with reference toFormula I, L is selected from the group consisting of *—(CHR₃)₁₋₃—,*—CHR₃N(R₂)—, *—CHR₃O—, *—CHR₃S—, *—CHR₃S(O)—, *—C(O)—, *—C(O)N(R₂)—,*—N(R₂)—, *—N(R₂)CHR₃—, *—N(R₂)C(O)—, *—N(R₂)C(O)N(R₂)—, *—N(R₂)S(O)₂—,wherein each R₂ is independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, R—C₀₋₄alkylene, andR—C₀₋₄alkylene-C(O)—, wherein each R is independently selected from thegroup consisting of hydroxyl, C₁₋₄alkoxy, amino, C₁₋₄alkylamino,di-C₁₋₄alkylamino, C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, andC₅₋₆heteroaryl, wherein said C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl andC₅₋₆heteroaryl are each unsubstituted or substituted with 1-2substituents independently selected from the group consisting ofC₁₋₄alkyl, halo, amino, hydroxyl, C₁₋₄alkoxy, oxo, and C₅₋₆heteroaryl.

In another variation, L is selected from the group consisting of*—(CHR₃)₁₋₃—, *—CHR₃N(R₂)—, *—CHR₃O—, *—CHR₃S—, *—CHR₃S(O)—, *—C(O)—,*—C(O)N(R₂)—, *—N(R₂)—, *—N(R₂)CHR₃—, *—N(R₂)C(O)—, *—N(R₂)C(O)N(R₂)—,*—N(R₂)S(O)₂—, wherein each R₂ is independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, R—C₀₋₄alkylene, wherein R is selectedfrom the group consisting of C₁₋₄alkoxy, C₁₋₄alkylamino,di-C₁₋₄alkylamino, C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl andC₅₋₆heteroaryl, wherein the C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl andC₅₋₆heteroaryl of R are each unsubstituted or substituted with 1-2substituents independently selected from the group consisting of halo,amino, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxy, oxo, and C₅₋₆heteroaryl.

In another variation, L is selected from the group consisting of*—C(O)N(R₂)—, and *—N(R₂)C(O)—, wherein each R₂ is independentlyselected from hydrogen, C₁₋₆alkyl, and R—C₀₋₄alkylene, and wherein R isselected from the group consisting of C₁₋₄alkylamino, C₃₋₆cycloalkyl,C₄₋₆heterocycloalkyl and C₅₋₆heteroaryl, each of which is unsubstitutedor substituted with 1-2 substituents independently selected from thegroup consisting of halo, amino, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxy, oxo,and C₅₋₆heteroaryl

In still another variation, L is selected from the group consisting of*—CH(CH₃)—, *—CH₂CH₂—, —*—CH₂N(CH₃)—, *—CH₂N(C(O)(CH₂)₁₋₂NH(CH₃))—,*—CH₂N(C(O)—(CH₂)₁₋₂NH₂)—, *—CH₂N((C(O)—(CH₂)₁₋₂N(CH₃)₂)—,*—CH₂N(C(O)(CH₂)₁₋₂OH)—, *—CH(CH₃)N(CH₃)—, *—CH₂O—, *—CH₂S—, *—CH₂S(O)—,*—C(O)—, *—C(O)N(CH₃)—, *—C(O)N(CH₂CH₃)—, *—C(O)N(CH(CH₃)₂)—,*—C(O)N(C(CH₃)₃)—, *—C(O)N(CH₂CH(CH₃)₂)—, *—C(O)N(CH(CH₃)CH₂CH₃)—,*—C(O)N(CH₂CH₂OCH₃)—, *—C(O)N(NH(CH₃))—, *—C(O)N(CH₂CH₂N(CH₃)₂)—,*—C(O)N(CH₃)CH₂—, *—NHCH₂—, *—N(CH₃)CH₂—,*—N(CH₂-tetrahydropyran-4-yl)-C(O)—,*—N(CH₃)C(O)—, *—N(CH₃)C(O)NH—,*—N(CH₃)S(O)₂—, *—C(O)N((CH₂)₀₋₁-cyclopropyl)-,*—C(O)N((CH₂)₀₋₁-cyclobutyl)-, *—C(O)N((CH₂)₀₋₁-cyclopentyl)-,*—C(O)N((CH₂)₀₋₁-cyclohexyl)-, *—C(O)N(CH₂-tetrahydropyran-4-yl)-,*—C(O)N((CH₂)₂-(1,1-dioxidothiomorpholino-4-yl))-,*—C(O)N(CH₂-1,1-dioxidothiomorpholino-4-yl)-,*—C(O)N((CH₂)₂-tetrahydropyran-4-yl))-,*—C(O)N((CH₂)₁₋₂-morpholin-4-yl)-, *—C(O)N(oxetan-3-yl)-,*—C(O)N(CH₂-oxetan-3-yl)-, *—C(O)N(CH(CH₃)—CH₂-1-H-pyrazoly-1-yl)-,*—CH₂N(C(O)—(CH₂)₁₋₂-morpholinyl))-,*—CH₂N(C(O)—(CH₂)₁₋₂-4-methylpiperizin-1-yl)),*—CH₂N(C(O)—(CH₂)₁₋₂-tetrahydropyran-4-yl)-, and*—CH₂N(C(O)(CH₂)₁₋₂-oxetan-3-yl)-.

In still another variation, L is selected from the group consisting of*—CH(CH₃)—, *—CH₂CH₂—, —*—CH₂N(CH₃)—, *—CH(CH₃)N(CH₃)—, *—CH₂O—,—*—CH₂S—, —*—CH₂S(O)—, *—C(O)—, *—C(O)N(CH₃)—, *—C(O)N(CH₂CH₃)—,*—C(O)N(CH(CH₃)₂)—, *—C(O)N(CH₃)CH₂—, *—C(O)N(CH₂CH₂OCH₃)—,*—C(O)N(NH(CH₃))—, *—C(O)N(CH₂CH₂N(CH₃)₂)—, *—NHCH₂—, *—N(CH₃)CH₂—,*—N(CH₂-tetrahydropyran-4-yl)-C(O)—,*—N(CH₃)C(O)—, *—N(CH₃)C(O)NH—,*—N(CH₃)S(O)₂—, *—C(O)N((CH₂)₀₋₁-cyclopropyl)-,*—C(O)N(CH₂-tetrahydropyran-4-yl)-, *—C(O)N(oxetan-3-yl)-, and*—C(O)N(CH(CH₃)CH₂-(1-H-pyrazoly-1-yl))-.

In a further variation, L is selected from the group consisting of*—C(O)N(CH₃)—, *—C(O)N(CH₂CH₃)—, *—C(O)N(CH(CH₃)₂)—, *—C(O)N(C(CH₃)₃)—,*—C(O)N(CH₂CH(CH₃)₂)—, *—C(O)N(CH(CH₃)CH₂CH₃)—,*—C(O)N((CH₂)₀₋₁-cyclopropyl)-, *—C(O)N((CH₂)₀₋₁-cyclobutyl)-,*—C(O)N((CH₂)₀₋₁-cyclopentyl)-, and *—C(O)N((CH₂)₀₋₁-cyclohexyl)-.

In still another further variation, L is selected from the groupconsisting of *—C(O)N(CH₃)—*—C(O)N(CH₂CH₃)—, *—C(O)N(CH(CH₃)₂)—,*—C(O)N(NH(CH₃))—, and *—N(CH₃)C(O)—.

In a particular variation, L is *—C(O)N(CH₃)— or *—N(CH₃)C(O)—. In aparticular variation, L is *—C(O)N(CH₃)—. In another particularvariation, L is *—N(CH₃)C(O)—. In another particular variation, L is*—C(O)N(CH₂CH₃)—. In another particular variation, L is*—C(O)N(CH(CH₃)₂)—. In another particular variation, L is*—C(O)N(NH(CH₃))—. In another particular variation, L is*—N((CH₂)₀₋₂)-tetrahydropyran-4-yl)-C(O)—. In still another particularvariation, L is *—C(O)—. In still another particular variation, L is—CH(CH₃)—. In yet still another particular variation, L is*—C(O)N(CH₂-cyclopropyl)-. In yet still another particular variation, Lis *—C(O)N(CH₂-cyclopropyl)-.

In still another embodiment of the compounds of the invention, withreference to any one of the above embodiments and variations, Ring A isselected from the group consisting of phenyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, pyrrolopyridinyl, indazolyl, each of which isunsubstituted or substituted by (R₁)_(n).

In one variation, Ring A is selected from the group consisting of

each of which is unsubstituted or substituted by (R₁)_(n). In anotherparticular variation, Ring A is selected from the group consisting of

each unsubstituted or substituted by 1 to 2 R₁ groups.

In a particular variation, -Ring A-R₁ is of the formula

In another particular variation, Ring A is of the formula

In yet another particular variation, -Ring A-R₁ is of the formula

In yet still another particular variation, Ring A is of the formula

In another embodiment of the compounds of the invention, with referenceto any one of the above embodiments and variations, Ring C is selectedfrom the group consisting of

each of which is unsubstituted or substituted by (R₁₇)_(p).

In one variation, Ring C is selected from the group consisting of phenyland pyridinyl, each unsubstituted or substituted by (R₁₇)_(p).

In another variation, -Ring C—R₁₇ is of the formula

In still another variation, -Ring C—R₁₇ is of the formula

In yet another variation, -Ring C—R₁₇ is of the formula

In still another embodiment of the compounds of the invention, withreference to any one of the above embodiments and variations, each R₁ isindependently selected from the group consisting of fluoro, chloro,cyano, methyl, trifluoromethyl, methoxy, —NH₂, —C(O)NH₂, —C(O)NH(CH₃),—C(O)N(CH₃)₂, —NHC(O)CH₃, —NHC(O)CH₂NH₂, —NHC(O)CH(NH₂)(CH₃),—NHC(O)CH(NH₂)(cyclohexyl), —NHC(O)CH(NH₂)CH(CH₃)₂, —NHC(O)CH(CH₃)₂,

In one variation, each R₁ is independently selected from the groupconsisting of trifluoromethyl, cyano, —NH₂—, —C(O)NH₂, —C(O)NHCH₃,—C(O)N(CH₃)₂, and —NHC(O)CH(NH₂)(CH₃). In another variation, R₁ istrifluoromethyl. In another variation, R₁ is —NH₂. In still anothervariation, R₁ is —C(O)NH₂. In yet another variation, R₁ is —C(O)NHCH₃.In yet another variation, R₁ is —C(O)N(CH₃)₂. In still yet anothervariation R₁ is NH₂.

In another embodiment of the compound of the invention, with referenceto any one of the above embodiments and variations, each R₁₇ isindependently selected from the group consisting of cyano, halo,C₁₋₄alkyl, haloC₁₋₄alkyl, —SO₂—C₁₋₄alkyl, and C₃₋₆cycloalkyl.

In one variation, each R₁₇ is independently selected from the groupconsisting of cyano, fluoro, chloro, methyl, trifluoromethyl,1,1-difluoroethyl, methylsulfonyl, and cyclopropyl.

In another variation, each R₁₇ is independently selected from the groupconsisting of cyano, chloro, fluoro, methylsulfonyl, andtrifluoromethyl.

In one particular variation, at least one of R₁₇ is cyano. In anotherparticular variation, at least one of R₁₇ is trifluoromethyl. In anotherparticular variation, R₁₇ is chloro or fluoro. In still anothervariation, R₁₇ is methylsulfonyl. In still another variation, R₁₇ ismethyl or fluoro. In yet still another variation, R₁₇ is cyano.

In another embodiment of the compound of the invention according to anyone of the above embodiments and variations, n is 1 or 2. In anothervariation, n is 1. In another variation, n is 2.

In another embodiment of the compounds of the present invention, withreference to any one of the above embodiments and variations, p is 1, 2or 3. In another variation, p is 1. In still another variation, p is 1.In yet still another variation, p is 3.

In a particular embodiment of the compounds of the invention, or apharmaceutical acceptable salt, tautomer or stereoisomer thereof, thecompound is of Formula Ia:

wherein

-   -   n is 1 or 2;    -   Ring A is phenyl, pyridinyl, or pyrimidinyl;    -   Ring C is phenyl or pyridinyl;    -   L is *—C(O)NR₂— or *—NR₂C(O)—, wherein R₂ is selected from        hydrogen, C₁₋₄alkyl, C₁₋₄alkylamino-(C₀₋₄)alkylene,        C₃₋₆cycloalkyl-(C₀₋₄)alkylene,        C₄₋₆heterocycloalkyl-(C₀₋₄)alkylene, wherein the        C₄₋₆heterocycloalkyl is selected from the group consisting of        piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,        and oxetanyl, and wherein the C₃₋₆cycloalkyl is selected from        cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;    -   each R₁ is independently *—C(O)NR₇R₈ or —NH₂—, wherein R₇ and R₈        are each independently hydrogen or C₁₋₄alkyl; and    -   R₁₇ is selected from the group consisting of cyano, halo, —NH₂—,        —C(O)NH₂, —C(O)NH(CH₃), and —C(O)N(CH₃)₂.

In one variation of the compounds of the present invention, withreference to the particular embodiment above, -Ring A-R₁ is of theformula

In another variation, -Ring A-R₁ is of the formula

In another variation of the compounds of the present invention, withreference to the particular embodiment and any one of the variationsabove, -Ring C—R₁₇ is of the formula

In another variation, -Ring C—R₁₇ is of the formula

In still another variation of the compounds of the present invention,with reference to the particular embodiment or any one of the variationsabove, L is *—C(O)N(CH₃)— or *—N(CH₃)C(O)—. In another variation, L is*—C(O)NH(CH₃)—, *—C(O)N(CH₂CH₃)—, *—C(O)N(CH(CH₃)₂)—, *—C(O)N(NH(CH₃))—,or *—NH(CH₃)C(O)—. In another variation, L is *—C(O)N(CH₃)— In anothervariation, L is *—N(CH₃)C(O)—. In another variation, L is*—C(O)N(CH₂CH₃)—. In another variation, L is *—C(O)N(CH(CH₃)₂)—. Inanother variation, L is *—C(O)N(NH(CH₃))—, In still another variation, Lis *—C(O)N(CH₂-cyclopropyl)-. In still another variation, L is*—C(O)N(cyclopropyl)-.

In still another variation of the compounds of the present invention,with reference to the particular embodiment or any one of the variationsabove, R₁ is —NH₂—. In another variation, R₁ is *—C(O)NH₂. In anothervariation, R₁ is —C(O)NH₂. In still another variation, R₁ is —C(O)NCH₃.

In still another variation of the compounds of the present invention,with reference to the particular embodiment or any one of the variationsabove, R₁₇ is cyano. In another variation R₁₇ is halo.

Particular examples of compounds or a pharmaceutically acceptable salt,tautomer or stereoisomer thereof, according to the present inventioninclude, but are not limited to:N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)aniline;N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)aniline;N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)yridine-2-amine;5-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;5-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;5-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;5-(((4-fluorophenyl)sulfinyl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;3-(4-(1H-pyrazol-5-yl)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;(S)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)benzamide;4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)benzamide;4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide;4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide;3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-N-(5-(methylsulfonyl)pyridine-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-amine;N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-amine;N-methyl-6-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)nicotinamide;N-methyl-5-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)picolinamide;4-cyano-N-((tetrahydro-2H-pyran-4-yl)methyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-(2-aminoacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(S)-3-(4-(2-amino-3-methylbutanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(S)-3-(4-(2-amino-2-cyclohexylacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-fluorophenyl)-1-methyl-1-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)urea;6-(1,1-difluoroethyl)-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide;6-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide;4-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;5-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide;N-methyl-4-(methylsulfonyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-aminopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-chloro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-(3-(4-carbamoylphenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylbenzamide;4-fluoro-N-methyl-N-(3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-3-(5-methoxypyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-fluorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;N-(4-cyanophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)phenyl)acetamide;3-(4-acetamidophenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-fluoropyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-amino-3,5-dimethylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-methylpyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-cyanopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-methoxypyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-(5-(1-(4-cyanophenyl)-2-methylhydrazinecarbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylpicolinamide;N-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-methyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-Amino-6-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Chlorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-Carbamoylphenyl)-N-(4-chlorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-((5-Cyanopyridin-2-yl)(methyl)carbamoyl)pyrazolo[1,5-a]pyridin-3-yl)benzoicacid;N-(5-Cyanopyridin-2-yl)-3-(4-((2-hydroxyethyl)carbamoyl)phenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-Methyl-3-(4-(methylcarbamoyl)phenyl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-((2-Aminoethyl)carbamoyl)phenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-Carbamoylphenyl)-N-(4-cyanophenyl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-Chloro-5-(methylsulfonamido)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(2-Aminopyridin-4-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Chlorophenyl)-N-methyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-(2-hydroxyethyl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-(2-Aminoethoxyl)pyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclobutyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-methyl-3-(4-(piperidin-4-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-methyl-3-(4-((2-(methylamino)ethyl)carbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-3-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Chlorophenyl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-(cyclopropylmethyl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(tert-Butyl)-N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-Carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(isopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(6-Methoxypyridin-3-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(cyclopropylcarbamoyl)phenyl)pyrazolo[1,5a]pyridine-5-carboxamide;N-(5-Chloropyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Cyclopropyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopentyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(ethylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;6-(N-Cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamido)nicotinic acid;N-(5-Carbamoylpyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Cyclopropyl-N-(3,4-difluorophenyl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(oxetan-3-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Cyclopropyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-Carbamoylphenyl)-N-cyclopropyl-N-(3,4-difluorophenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Cyclopropyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-cyclopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-Carbamoylpyridin-3-yl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-Carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-ethyl-3-(4-[N-methylsulfamoyl]phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-cyclopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-Carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Chlorophenyl)-N-cyclopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-Cyano-N-cyclopropyl-N-(3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide;N-(5-Cyanopyridin-2-yl)-N-isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyano-6-methoxypyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-ethyl-3-(6-[methylcarbamoyl]pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-fluoropyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Isopropyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclobutyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-fluoropyridin-2-yl)-N-isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-3-(6-(methylcarbamoyl)pyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-ethyl-3-(4-(methylsulfonyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-N-(5-fluoropyridin-2-yl)-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-cyclobutyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;NN-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyano-6-(2-hydroxyethoxyl)pyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-(N-(5-Cyanopyridin-2-yl)-N-methylsulfamoyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;4-(5-(N-(5-Cyanopyridin-2-yl)-N-cyclopropylsulfamoyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;4-(5-(N-(5-cyanopyridin-2-yl)-N-cyclopropylsulfamoyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide.

Particular examples of the compounds or a pharmaceutically acceptablesalt, tautomer or stereoisomer thereof, according to the presentinvention include, but are not limited to:3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;and3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide.

Another particular examples of the compounds or a pharmaceuticallyacceptable salt, tautomer or stereoisomer thereof, according to thepresent invention include, but are not limited to:N-(5-Cyanopyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-(5-(1-(4-cyanophenyl)-2-methylhydrazinecarbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylpicolinamide;N-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;andN-ethyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt. It is further note that thecompounds of the present invention may be a mixture of stereoisomers, orthe compound may comprise a single stereoisomer.

Further compounds of the invention are detailed in the Examples, infra.

In another aspect, the present invention is directed to a pharmaceuticalcomposition which includes as an active ingredient a compound accordingto any one of the above embodiments and variations in combination with apharmaceutically acceptable carrier, diluent or excipient.

In one embodiment, the pharmaceutical composition further includes asecond agent which can be a kinase inhibitor, an anti-malarial drug oran anti-inflammatory agent.

In another embodiment, the pharmaceutical composition includes anantimalarial drug as a second agent. The selections for the antimalarialdrug may includes, but are not limited to, artemisinin, artemether,artesunate, arteflene, dihydroartemisinin, chlorproguanil, trimethoprim,chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil,lumefantrine, piperaquine, pyronaridine, halofantrine,pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine,amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine,arterolane, and pyronaridine.

In another embodiment, the pharmaceutical composition is a solidformulation adapted for oral administration. In another embodiment, thecomposition is a liquid formulation adapted for oral administration. Inyet another embodiment, the composition is a tablet. In still anotherembodiment, the composition is a liquid formulation adapted forparenteral administration.

In yet another embodiment, the pharmaceutical composition is adapted foradministration by a route selected from the group consisting of orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In another aspect, the present application is directed to a compound ora pharmaceutical composition according to any one of the aboveembodiments and variations for use in a therapeutic application.

In another aspect, the present application is directed to a compound ora pharmaceutical composition according to any one of the aboveembodiments and variations for use as a medicament.

In yet another aspect, the present invention is directed to a method fortreating, preventing, inhibiting, ameliorating, or eradicating thepathology and/or symptomology of a disease caused by a Plasmodiumparasite. The method involves administering to a subject atherapeutically effective amount of a compound or a pharmaceuticalcomposition according to the above embodiments and variations. Inaddition, the administering may be in combination with a second agent.

In one embodiment of the method of the invention, the method is directedto treatment of malaria; particularly malaria caused by the parasitesPlasmodium falciparum, Plasmodium vivax, Plasmodium ovale, andPlasmodium malaria; more particularly, the parasite Plasmodiumfalciparum. Further, the Plasmodium parasite can be at the blood stagesor at the hepatic stages.

In the treatment method of the invention, the compounds orpharmaceutical compositions may be administered with prior to,simultaneously with, or after a second agent. The second agent can be akinase inhibitor, an anti-malarial drug or an anti-inflammatory agent.In one particular variation of the method, the second agent is ananti-malarial drug. The selection of the antimalarial drug, includes,but is not limited to, artemisinin, artemether, artesunate, arteflene,dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine,mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine,piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine,quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine,sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, andpyronaridine.

In another aspect, the invention is directed to a compound, salt,steroisomer, or pharmaceutical composition thereof, according to any oneof the above embodiments or variation, for treating, preventing,inhibiting, ameliorating, or eradicating the pathology and/orsymptomology of a disease caused by a Plasmodium parasite. In oneembodiment, the disease is malaria caused by the Plasmodium parasitePlasmodium falciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodiummalaria; particularly, the parasite Plasmodium falciparum. Further, thePlasmodium parasite can be at the blood stages, or the Plasmodiumparasite can be at the hepatic stages.

In still another aspect, the present invention is directed to the use ofthe compound, or a salt, a stereoisomer, or a pharmaceutical compositionthereof, according to the any one of the above embodiments or variationsin the manufacture of a medicament for treating, preventing, inhibiting,ameliorating, or eradicating the pathology and/or symptomology of adisease caused by a Plasmodium parasite. In one embodiment, themedicament is for treating malaria causes by the parasite Plasmodiumfalciparum, Plasmodium vivax, Plasmodium ovale, or Plasmodium malaria;in particular, the parasite Plasmodium falciparum. Further, thePlasmodium parasite can be at the blood stages or at the hepatic stages.

The medicament, in addition to the compound of the invention, mayfurther include a second agent. The second agent may be a kinaseinhibitor, an anti-malarial drug or an anti-inflammatory agent. In oneparticular embodiment, the second agent is an anti-malarial drugselected from artemisinin, artemether, artesunate, arteflene,dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine,mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine,piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine,quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine,sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, andpyronaridine.

In another aspect, the invention is related to a kit which comprises acompound of any one of the above embodiments and variations, andoptionally a second therapeutic agent. In one particular variation, thekit comprises the compound in a multiple dose form.

Enumerated Embodiments

Various enumerated embodiments of the invention are described herein. Itwill be recognized that features specified in each embodiment may becombined with other specified features to provide further embodiments ofthe present invention.

In a first embodiment, the invention provides a compound of the formula(I), or a pharmaceutical acceptable salt, tautomer or stereoisomerthereof,

-   -   wherein:        -   n is 0, 1, 2 or 3;        -   p is 0, 1, 2 or 3;        -   L is selected from the group consisting of *—(CHR₃)₁₋₃—,            *—CHR₃N(R₂)—, *—CHR₃O—, *—CHR₃S—, *—CHR₃S(O)—,            *—CHR₃N(R₂)CHR₃—, *—C(O)—, *—C(O)N(R₂)—, *—C(O)N(R₂)CHR₃—,            *—N(R₂)—, *—N(R₂)CHR₃—, *—N(R₂)C(O)—, *—N(R₂)C(O)N(R₂)—, and            *—N(R₂)S(O)₂—, wherein            -   * represents the point of attachment of L to the                pyrazolo[1,5-a]pyridine fused ring depicted in Formula                I;            -   each R₂ is independently selected from the group                consisting of hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,                R—C₀₋₄alkylene, and R—C₀₋₄alkylene-C(O)—, wherein R is                selected from the group consisting of hydroxyl,                C₁₋₄alkoxy, amino, C₁₋₄alkylamino, C₃₋₆cycloalkyl,                C₄₋₆heterocycloalkyl, and C₅₋₆heteroaryl, wherein the                C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, and C₅₋₆heteroaryl                of R are each unsubstituted or substituted with 1-2                substituents independently selected from the group                consisting of halo, amino, hydroxyl, C₁₋₄alkyl,                C₁₋₄alkoxy, oxo, and C₅₋₆heteroaryl; and            -   each R₃ is independently selected from the group                consisting of hydrogen and C₁₋₄alkyl,        -   Ring A is selected from the group consisting of C₆₋₁₀aryl            and C₃₋₁₀heteroaryl;        -   Ring C is selected from the group consisting of C₆₋₁₀aryl,            C₅₋₁₀heteroaryl, C₅₋₇cycloalkyl, C₅₋₇heterocycloalkyl, and a            fused bicyclyl comprising a C₅₋₆heterocycloalky fused to a            phenyl;        -   each R₁ is independently selected from the group consisting            of halo, cyano, amino, C₁₋₄alkyl, C₁₋₄alkoxyl,            halo-C₁₋₄alkyl, —C(O)NR₇R₈, —NHC(O)R₁₁, phenyl, and            C₅₋₆heteroaryl; wherein            -   the phenyl and C₅₋₆heteroaryl are each unsubstituted or                substituted with 1-2 substituents independently selected                from the group consisting of C₁₋₄alkyl, amino, halo, and                C₁₋₄alkylamino;            -   R₇ and R₈ are each independently selected from hydrogen,                C₁₋₄alkyl and haloC₁₋₄alkyl;            -   R₁₁ is C₁₋₆alkyl unsubstituted or substituted with 1-2                substituents independently selected from the group                consisting of amino, C₃₋₆cycloalkyl and                C₄₋₆heterocycloalkyl; and        -   R₁₇ is selected from the group consisting of cyano, halo,            C₁₋₄alkyl, halo-C₁₋₄alkyl, oxo, C₃₋₆cycloalkyl, and            —SO₂—C₁₋₄alkyl.

Embodiment 2

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein L is selected from the groupconsisting of *—(CHR₃)₁₋₃—, *—CHR₃N(R₂)—, *—CHR₃O—, *—CHR₃S—,*—CHR₃S(O)—, *—C(O)—, *—C(O)N(R₂)—, *—N(R₂)—, *—N(R₂)CHR₃—,*—N(R₂)C(O)—, *—N(R₂)C(O)N(R₂)—, *—N(R₂)S(O)₂—, wherein

-   -   each R₂ is independently selected from the group consisting of        hydrogen, C₁₋₆alkyl, R—C₀₋₄alkylene, wherein R is selected from        the group consisting of C₁₋₄alkoxy, C₁₋₄alkylamino,        di-C₁₋₄alkylamino, C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl and        C₅₋₆heteroaryl, wherein the C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl        and C₅₋₆heteroaryl of R are each unsubstituted or substituted        with 1-2 substituents independently selected from the group        consisting of halo, amino, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxy, oxo,        and C₅₋₆heteroaryl.

Embodiment 3

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein L is selected from the groupconsisting of *—C(O)N(R₂)—, and *—N(R₂)C(O)—, wherein each R₂ isindependently selected from hydrogen, C₁₋₄alkyl, and R—C₀₋₄alkylene,wherein R is selected from the group consisting of C₁₋₄alkylamino,C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl and C₅₋₆heteroaryl, eachunsubstituted or substituted with 1-2 substituents independentlyselected from the group consisting of halo, amino, hydroxyl, C₁₋₄alkyl,C₁₋₄alkoxy, oxo, and C₅₋₆heteroaryl.

Embodiment 4

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein L is selected from the groupconsisting of *—CH(CH₃)—, *—CH₂CH₂—, —*—CH₂N(CH₃)—,*—CH₂N(C(O)(CH₂)₁₋₂NH(CH₃))—, *—CH₂N(C(O)—(CH₂)₁₋₂NH₂)—,*—CH₂N((C(O)—(CH₂)₁₋₂N(CH₃)₂)—, *—CH₂N(C(O)(CH₂)₁₋₂OH)—,*—CH(CH₃)N(CH₃)—, *—CH₂O—, *—CH₂S—, *—CH₂S(O)—, *—C(O)—, *—C(O)N(CH₃)—,*—C(O)N(CH₂CH₃)—, *—C(O)N(CH(CH₃)₂)—, *—C(O)N(C(CH₃)₃)—,*—C(O)N(CH₂CH(CH₃)₂)—, *—C(O)N(CH(CH₃)CH₂CH₃)—, *—C(O)N(CH₂CH₂OCH₃)—,*—C(O)N(NH(CH₃))—, *—C(O)N(CH₂CH₂N(CH₃)₂)—, *—C(O)N(CH₃)CH₂—, *—NHCH₂—,*—N(CH₃)CH₂—, *—N(CH₂-tetrahydropyran-4-yl)-C(O)—,*—N(CH₃)C(O)—,*—N(CH₃)C(O)NH—, *—N(CH₃)S(O)₂—, *—C(O)N((CH₂)₀₋₁-cyclopropyl)-,*—C(O)N(CH₂)₀₋₁-cyclobutyl)-, *—C(O)N((CH₂)₀₋₁-cyclopentyl)-,*—C(O)N((CH₂)₀₋₁-cyclohexyl)-, *—C(O)N(CH₂-tetrahydropyran-4-yl)-,*—C(O)N((CH₂)₂-(1,1-dioxidothiomorpholino-4-yl))-,*—C(O)N(CH₂-1,1-dioxidothiomorpholino-4-yl)-,*—C(O)N((CH₂)₂-tetrahydropyran-4-yl))-,*—C(O)N((CH₂)₁₋₂-morpholin-4-yl)-, *—C(O)N(oxetan-3-yl)-,*—C(O)N(CH₂-oxetan-3-yl)-, *—C(O)N(CH(CH₃)—CH₂-1-H-pyrazoly-1-yl)-,*—CH₂N(C(O)—(CH₂)₁₋₂-morpholinyl))-,*—CH₂N(C(O)—(CH₂)₁₋₂-4-methylpiperizin-1-yl),*—CH₂N(C(O)—(CH₂)₁₋₂-tetrahydropyran-4-yl)-, and*—CH₂N(C(O)(CH₂)₁₋₂-oxetan-3-yl)-.

Embodiment 5

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein L is selected from the groupconsisting of *—CH(CH₃)—, *—CH₂CH₂—, —*—CH₂N(CH₃)—, *—C(O)N(CH₂CH₃)—,*—C(O)N(CH(CH₃)₂)—, *—CH(CH₃)N(CH₃)—, *—CH₂O—, *—CH₂S—, —*—CH₂S(O)—,*—C(O)—, *—C(O)N(CH₃)—, *—C(O)N(CH₃)CH₂—, *—C(O)N(CH₂CH₂OCH₃)—,*—C(O)N(NH(CH₃))—, *—C(O)N(CH₂CH₂N(CH₃)₂)—, *—NHCH₂—, *—N(CH₃)CH₂—,*—N(CH₂-tetrahydropyran-4-yl)-C(O)—, *—N(CH₃)C(O)—, *—N(CH₃)C(O)NH—,*—N(CH₃)S(O)₂—, *—C(O)N((CH₂)₀₋₁-cyclopropyl)-,*—C(O)N(CH₂-tetrahydropyran-4-yl)-, *—C(O)N(oxetan-3-yl)-, and*—C(O)N(CH(CH₃)CH₂-(1-H-pyrazoly-1-yl))-.

Embodiment 6

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein L is *—C(O)N(CH₃)—,*—C(O)N(CH₂CH₃)—, *—C(O)N(CH(CH₃)₂)—, *—C(O)N(NH(CH₃))—, or*—N(CH₃)C(O)—.

Embodiment 7

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein L is *—C(O)N(cyclopropyl)-.

Embodiment 8

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein L is *—C(O)— or —CH(CH₃)—.

Embodiment 9

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiments 1 to 8, wherein Ring A is selectedfrom the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, pyrrolopyridinyl, and indazolyl, each of which isunsubstituted or substituted by (R₁)_(n).

Embodiment 10

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 8, wherein Ring A isselected from the group consisting of

each of which is unsubstituted or substituted by (R₁)_(n).

Embodiment 11

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 8, wherein -Ring A-R₁is of the formula

Embodiment 12

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 8, wherein -Ring A-R₁is of the formula

Embodiment 13

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 8, wherein -Ring A-R₁is of the formula

Embodiment 14

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 8, wherein Ring A isof the formula

Embodiment 15

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 14, wherein Ring C isselected from the group consisting of

each of which is unsubstituted or substituted by (R₁₇)_(p).

Embodiment 16

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 7 and 9-14, whereinRing C is selected from the group consisting of phenyl and pyridinyl,each of which is unsubstituted or substituted by (R₁₇)_(p).

Embodiment 17

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 7 and 9-14, wherein-Ring C—R₁₇ is of the formula

Embodiment 18

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 7 and 9-14, wherein-Ring C—R₁₇ is of the formula

Embodiment 19

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1-2, 4-5 and 8-14, wherein-Ring C—R₁₇ is of the formula

Embodiment 20

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 19, wherein each R₁ isindependently selected from the group consisting of fluoro, chloro,cyano, methyl, trifluoromethyl, methoxy, —NH₂, —C(O)NH₂, —C(O)NH(CH₃),—C(O)N(CH₃)₂, —NHC(O)CH₃, —NHC(O)CH₂NH₂, —NHC(O)CH(NH₂)(CH₃),—NHC(O)CH(NH₂)(cyclohexyl), —NHC(O)CH(NH₂)CH(CH₃)₂, —NHC(O)CH(CH₃)₂,

Embodiment 21

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 19, wherein each R₁ isindependently selected from the group consisting of trifluoromethyl,cyano, —NH₂—, —C(O)NH₂, —C(O)NHCH₃, and —C(O)N(CH₃)₂,

Embodiment 22

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 19, wherein R₁ istrifluoromethyl.

Embodiment 23

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 19, wherein R₁ is—NH₂.

Embodiment 24

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 19, wherein R₁ is—C(O)NH₂.

Embodiment 25

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 19, wherein R₁ is—C(O)NHCH₃.

Embodiment 26

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 19, wherein R₁ is—NHC(O)CH(NH₂)(CH₃).

Embodiment 27

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 26, wherein each R₁₇is independently selected from the group consisting of cyano, halo,C₁₋₄alkyl, haloC₁₋₄alkyl, —SO₂—C₁₋₄alkyl, and C₃₋₆cycloalkyl.

Embodiment 28

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1 to 26, wherein each R₁₇is independently selected from the group consisting of cyano, fluoro,chloro, methyl, trifluoromethyl, 1,1-difluoroethyl, methylsulfonyl, andcyclopropyl.

Embodiment 29

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1-7, 9-18 and 20-26, R₁₇ iscyano.

Embodiment 30

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1-7, 9-18 and 20-26, R₁₇ istrifluoromethyl

Embodiment 31

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1-7, 9-18 and 20-26,wherein R₁₇ is fluoro or chloro.

Embodiment 32

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1-7, 9-18 and 20-26,wherein R₁₇ is methylsulfonyl.

Embodiment 33

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to any one of embodiments 1-2, 4-5, 8-15 and 19,where each R₁₇ is methyl.

Embodiment 34

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein the compound is of FormulaIa

-   -   wherein        -   n is 1 or 2;        -   Ring A is phenyl, pyridinyl, or pyrimidinyl;        -   Ring C is phenyl or pyridinyl;        -   L is *—C(O)NR₂— or *—NR₂C(O)—, wherein R₂ is selected from            hydrogen, C₁₋₄alkyl, C₁₋₄alkylamino-(C₀₋₄)alkylene,            C₃₋₆cycloalkyl-(C₀₋₄)alkylene,            C₄₋₆heterocycloalkyl-(C₀₋₄)alkylene, wherein the            C₄₋₆heterocycloalkyl is selected from the group consisting            of piperazinyl, morpholinyl, thiomorpholinyl,            tetrahydropyranyl, and oxetanyl, and wherein the            C₃₋₆cycloalkyl is selected from cyclopropyl, cyclobutyl,            cyclopentyl and cyclohexyl;    -   each R₁ is independently *—C(O)NR₇R₈ or —NH₂—, wherein R₇ and R₈        are each independently hydrogen or C₁₋₄alkyl; and    -   R₁₇ is selected from the group consisting of cyano, halo, —NH₂—,        —C(O)NH₂, —C(O)NH(CH₃), and —C(O)N(CH₃)₂.

Embodiment 35

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 34, wherein -Ring A-R₁ is of theformula

Embodiment 36

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 34, wherein -Ring A-R₁ is of theformula

Embodiment 37

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiments 34-36, wherein -Ring C—R₁₇ is of theformula

Embodiment 38

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiments 34-36, wherein -Ring C—R₁₇ is of theformula

Embodiment 39

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiments 36-38, wherein L is *—C(O)NH(CH₃)—,*—C(O)N(CH₂CH₃)—, *—C(O)N(CH(CH₃)₂)—, *—C(O)N(NH(CH₃))—, or*—NH(CH₃)C(O)—.

Embodiment 40

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiments 36-38, wherein L is*—C(O)N(cyclopropyl)-Embodiment 41. A compound of the formula (I), or asalt, tautomer or stereoisomer thereof, according to embodiments 36-40,wherein R₁ is —NH₂—.

Embodiment 42

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiments 36-40, wherein R₁ is —C(O)NH₂ or—C(O)NCH₃.

Embodiment 43

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiments 36-42, wherein R₁₇ is cyano.

Embodiment 44

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiments 36-42, wherein R₁₇ is halo.

Embodiment 45

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein the compound is selectedfrom the group consisting of:N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)aniline;N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)aniline;N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)yridine-2-amine;5-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;5-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;5-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;5-(((4-fluorophenyl)sulfinyl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;3-(4-(1H-pyrazol-5-yl)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;(S)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)benzamide;4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)benzamide;4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide;4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide;3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)yridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-N-(5-(methylsulfonyl)pyridine-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-amine;N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-amine;N-methyl-6-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)nicotinamide;N-methyl-5-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)picolinamide;4-cyano-N-((tetrahydro-2H-pyran-4-yl)methyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-(2-aminoacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(S)-3-(4-(2-amino-3-methylbutanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(S)-3-(4-(2-amino-2-cyclohexylacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-fluorophenyl)-1-methyl-1-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)urea;6-(1,1-difluoroethyl)-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide;6-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide;4-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;5-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide;N-methyl-4-(methylsulfonyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-aminopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-chloro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-(3-(4-carbamoylphenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylbenzamide;4-fluoro-N-methyl-N-(3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-3-(5-methoxypyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-fluorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;N-(4-cyanophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)phenyl)acetamide;3-(4-acetamidophenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-fluoropyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-amino-3,5-dimethylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-methylpyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-cyanopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-methoxypyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-(5-(1-(4-cyanophenyl)-2-methylhydrazinecarbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylpicolinamide;N-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;andN-ethyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide.

Embodiment 46

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein the compound is selectedfrom the group consisting of:3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide.

Embodiment 47

A compound of the formula (I), or a salt, tautomer or stereoisomerthereof, according to embodiment 1, wherein the compound is selectedfrom the group consisting of:N-(5-Cyanopyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-(5-(1-(4-cyanophenyl)-2-methylhydrazinecarbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylpicolinamide;N-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;andN-ethyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide.

Embodiment 48

A pharmaceutical composition comprising at least one compound of any oneof embodiments 1 to 47 or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier, diluent or excipient.

Embodiment 49

A pharmaceutical composition according to embodiment 48 furthercomprising a second agent.

Embodiment 50

A pharmaceutical composition according to embodiment 49, wherein thesecond agent is an antimalarial drug selected from the group consistingof artemisinin, artemether, artesunate, arteflene, dihydroartemisinin,chlorproguanil, trimethoprim, chloroquine, quinine, mefloquine,amodiaquine, atovaquone, proguanil, lumefantrine, piperaquine,pyronaridine, halofantrine, pyrimethamine-sulfadoxine, quinacrine,pyrimethamine-dapsone, quinidine, amopyroquine, sulphonamides,primaquine, ferroquine, tafenoquine, arterolane, and pyronaridine.

Embodiment 51

A compound according to any one of embodiments 1 to 47 or apharmaceutical composition according to any one of embodiments 48-50 foruse as a medicament.

Embodiment 52

A method for treating, preventing, inhibiting, ameliorating, oreradicating the pathology and/or symptomology of a disease caused by aPlasmodium parasite, comprising administering to a subject atherapeutically effective amount of a compound according to any one ofembodiments 1 to 47 or a composition according to any one of embodiments48 to 50, wherein the administering may be in combination with a secondagent.

Embodiment 53

A method for treating, preventing, inhibiting, ameliorating, oreradicating the pathology and/or symptomology of a disease caused by aPlasmodium parasite, according to embodiment 52, wherein the disease ismalaria.

Embodiment 54

A method for treating, preventing, inhibiting, ameliorating, oreradicating the pathology and/or symptomology of a disease caused by aPlasmodium parasite according to embodiments 52-53, wherein thePlasmodium parasite is at the blood stages.

Embodiment 55

A method for treating, preventing, inhibiting, ameliorating, oreradicating the pathology and/or symptomology of a Plasmodium relateddisease caused by a Plasmodium parasite according to embodiments 52-53,wherein the Plasmodium parasite is at the hepatic stages.

Embodiment 56

A method for treating, preventing, inhibiting, ameliorating, oreradicating the pathology and/or symptomology of a Plasmodium relateddisease caused by a Plasmodium parasite according to embodiments 52-55,wherein the Plasmodium parasite is selected from group consisting ofPlasmodium falciparum, Plasmodium vivax, Plasmodium ovale, andPlasmodium malaria.

Embodiment 57

A method for treating, preventing, inhibiting, ameliorating, oreradicating the pathology and/or symptomology of a Plasmodium relateddisease caused by a Plasmodium parasite according to embodiments 52-55,wherein the Plasmodium parasite is Plasmodium falciparum.

Embodiment 58

A method for treating, preventing, inhibiting, ameliorating, oreradicating the pathology and/or symptomology of a Plasmodium relateddisease caused by a Plasmodium parasite according to embodiments 52-57,wherein the second agent is selected from a kinase inhibitor, ananti-malarial drug and an anti-inflammatory agent.

Embodiment 59

A method for treating, preventing, inhibiting, ameliorating, oreradicating the pathology and/or symptomology of a disease caused byPlasmodium parasite according to embodiment 58, wherein theanti-malarial drug is selected from the group consisting of artemisinin,artemether, artesunate, arteflene, dihydroartemisinin, chlorproguanil,trimethoprim, chloroquine, quinine, mefloquine, amodiaquine, atovaquone,proguanil, lumefantrine, piperaquine, pyronaridine, halofantrine,pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine,amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine,arterolane, and pyronaridine.

Embodiment 60

A method for treating, preventing, inhibiting, ameliorating, oreradicating the pathology and/or symptomology of a disease caused byPlasmodium parasite according to embodiments 52-59, wherein the compoundis administered prior to, simultaneously with, or after the secondagent.

Embodiment 61

A compound according to any one of embodiments 1-46 or a compositionaccording to any one of embodiments 48 to 50 for treating, preventing,inhibiting, ameliorating, or eradicating the pathology and/orsymptomology of a disease caused by a Plasmodium parasite.

Embodiment 62

Use of a compound according to any one of embodiments 1-47 or apharmaceutical composition according to embodiments 48-50 in themanufacture of a medicament for treating, preventing, inhibiting, orameliorating the pathology and/or symptomology of a disease caused by aPlasmodium parasite, wherein the medicament may further include a secondagent.

As used herein, the term “an optical isomer” or “a stereoisomer” refersto any of the various stereo isomeric configurations which may exist fora given compound of the present invention and includes geometricisomers. It is understood that a substituent may be attached at a chiralcenter of a carbon atom. The term “chiral” refers to molecules whichhave the property of non-superimposability on their mirror imagepartner, while the term “achiral” refers to molecules which aresuperimposable on their mirror image partner. Therefore, the inventionincludes enantiomers, diastereomers or racemates of the compound.“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term is used to designate a racemic mixture whereappropriate. “Diastereoisomers” are stereoisomers that have at least twoasymmetric atoms, but which are not mirror-images of each other. Theabsolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain compounds described herein contain one ormore asymmetric centers or axes and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possible isomers oras mixtures thereof, for example as pure optical isomers, or as isomermixtures, such as racemates and diastereoisomer mixtures, depending onthe number of asymmetric carbon atoms. The present invention is meant toinclude all such possible isomers, including racemic mixtures,diasteriomeric mixtures and optically pure forms. Optically active (R)-and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. If the compoundcontains a double bond, the substituent may be E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans-configuration. All tautomeric formsare also intended to be included.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H and ¹⁴C, or those into which non-radioactiveisotopes, such as ²H and ¹³C are present. Such isotopically labelledcompounds are useful in metabolic studies (with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques,such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically-labeled compounds of formula (I) cangenerally be prepared by conventional techniques known to those skilledin the art or by processes analogous to those described in theaccompanying Examples and Preparations using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, excipients, disintegrationagents, lubricants, sweetening agents, flavoring agents, dyes, and thelike and combinations thereof, as would be known to those skilled in theart (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, 1990, pp. 1289-1329). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviate, inhibit,prevent and/or ameliorate a condition, or a disorder or a disease (i)mediated by Plasdmodium or (ii) associated with Plasdmodium activity, or(iii) characterized by activity (normal or abnormal) of Plasdmodium or(2) reduce or inhibit the activity of Plasdmodium; or (3) reduce orinhibit the growth of Plasdmodium. In another non-limiting embodiment,the term “a therapeutically effective amount” refers to the amount ofthe compound of the present invention that, when administered to a cell,or a tissue, or a non-cellular biological material, or a medium, iseffective to at least partially reducing or inhibiting the activity ofPlasdmodium; or at least partially reducing or inhibiting the growth ofPlasdmodium.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95 enantiomeric excess, or at least 99% enantiomeric excess in the(R)- or (S)-configuration. Substituents at atoms with unsaturated doublebonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

Pharmacology and Administration

Compounds of the invention are useful in the treatment and/or preventionof infections such as those caused by Plasmodium falciparum; Plasmodiumvivax; Plasmodium ovale; and Plasmodium malaria, Trypanosoma cruzi andparasites of the Leishmania genus, such as, for example, Leishmaniadonovani.

Plasmodia spp. which causes malaria belongs to the phylum, Apicomplexa,which is a large and diverse group of protists that are human or animalparasites. These parasites are unicellular, spore-forming, and possessmotile structures such as flagella or pseudopods at certain gametestages. Most of these parasites possess a unique organelle calledapicoplast and an apical comples structure involved in penetrating ahost's cell. The pathogenesis associated the diseases caused by theseparasites is due to repeated cycles of host-cell invasion, intracellularreplication and host-cell lysis. Therefore, understanding parasiteproliferation is essential for development of novel drugs and vaccines,for example, to treat malaria.

In vertebrate hosts, the parasite undergoes two main phases ofdevelopment, the hepathocytic and erythrocytic phases, but it is theerythrocytic phase of its life cycle that causes severe pathology.During the erythrocytic phase, the parasite goes through a complex butwell synchronized series of stages, suggesting the existence of tightlyregulated signaling pathways.

Calcium serves as an intracellular messenger to control synchronizationand development in the erythrocytic life phase. The Plasmodium spp.genomes reveal many sequence identities with calcium binding/sensingprotein motifs that include Pf39, calmodulin, and calcium dependentprotein kinases (CDPKs). Plasmodium CDPKs, Plasmodium CDPK3 and 4, havebeen shown to be involved in mosquito infection. CDPK4 has beendemonstrated to be essential for the sexual reproduction in the midgutof mosquito by translating the calcium signal into a cellular responseand regulating cell cycle progression in the male gametocyte. CDPK3regulates ookinete gliding motility and penetration of the layercovering the midgut epithelium. P. falciparum CDPK1 (PfCDPK1) isexpressed during late schizogony of blood stage and in the infectioussporozoite stage and is secreted to the parasitophorous vacuole by anacylation-dependent mechanism. It can be myristoylated and is abundantlyfound in detergent-resistant membrane fractions isolated fromschizogony-phase parasites. Ontology based pattern identificationanalysis reveals that PfCDPK1 is clustered with genes associated witheither parasite egress or erythrocyte invasion. Direct inhibition ofPfCDPK1 can arrest the parasite erythrocytic life cycle progression inthe late schizogony phase.

Therefore, kinase activity is distributed in all the stages of P.falciparum parasite maturation and kinase inhibitors of the presentinvention can be used for treating Plasmodium related diseases.

The in vitro cellular assay, infra, can be used to assess the activityof compounds of the invention against a variety of malarial parasitestrains.

In accordance with the foregoing, the present invention further providesa method for preventing or treating malaria in a subject in need of suchtreatment, which method comprises administering to the subject atherapeutically effective amount of a compound selected from Formula Iand Ia or a pharmaceutically acceptable salt, tautomer or stereoisomer,thereof. The required dosage will vary depending on the mode ofadministration, the particular condition to be treated and the effectdesired.

In general, compounds of the invention will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g. humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered, e.g.in divided doses up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from ca. 1 to 50 mg activeingredient.

Compounds of the invention can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present invention in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present invention witha carrier. A carrier can include absorbable pharmacologically acceptablesolvents to assist passage through the skin of the host. For example,transdermal devices are in the form of a bandage comprising a backingmember, a reservoir containing the compound optionally with carriers,optionally a rate controlling barrier to deliver the compound to theskin of the host at a controlled and predetermined rate over a prolongedperiod of time, and means to secure the device to the skin. Matrixtransdermal formulations may also be used. Suitable formulations fortopical application, e.g., to the skin and eyes, are preferably aqueoussolutions, ointments, creams or gels well-known in the art. Such maycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

Compounds of the invention can be administered in therapeuticallyeffective amounts in combination with one or more therapeutic agents(pharmaceutical combinations). Non-limiting examples of compounds whichcan be used in combination with compounds of the invention are knownanti-malarial drugs, for example, artemisinin, artemether, artesunate,arteflene, dihydroartemisinin, chlorproguanil, trimethoprim,chloroquine, quinine, mefloquine, amodiaquine, atovaquone, proguanil,lumefantrine, piperaquine, pyronaridine, halofantrine,pyrimethamine-sulfadoxine, quinacrine, pyrimethamine-dapsone, quinidine,amopyroquine, sulphonamides, primaquine, ferroquine, tafenoquine,arterolane, and pyronaridine, etc.

Where the compounds of the invention are administered in conjunctionwith other therapies, dosages of the co-administered compounds will ofcourse vary depending on the type of co-drug employed, on the specificdrug employed, on the condition being treated and so forth.

The invention also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of the invention asdisclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula I and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the 2compounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of 3 or more activeingredients.

Biological Assays

The activity of a compound according to the present invention forinhibition of parasitemai in infected blood cells and liver cells can beassessed by the following assays. It is understood that the assaysillustrate the invention without in any way limiting the scope of theinvention.

Assay for P. falciparum Proliferation in Infected Human Blood Cells

Compounds of the invention can be assayed to measure their capacity toinhibit proliferation of P. falciparum parasitemia in infected red bloodcells. This parasite proliferation assay measures the increase inparasite DNA content using a DNA intercalating dye, SYBR Green®(INVITROGEN®) which has a high affinity for double stranded DNA.

NF54 or 3D7 P. falciparum strain is grown in complete culturing mediauntil parasitemia reaches 3% to 8% with O+ human erythrocytes. Theselection of either strain is of convenience (3D7 is a clone of NF54)and does not make a difference to the assay. 20 μl of screening media isdispensed into 384 well assay plates. 50 nl of compounds of theinvention (in DMSO), including antimalarial controls (mefloquine,pyrimethamine and artemisinin), are then transferred into the assayplates, as well as DMSO alone to serve as a negative control forinhibition. Then 30 μl of a suspension of a NF54 or 3D7 P. falciparuminfected erythrocytes in screening media is dispensed into the assayplates such that the final hematocrit is 2.5% with a final parasitemiaof 0.3%. The plates are placed in a 37° C. incubator for 72 hours in alow oxygen environment containing 93% N₂, 4% CO₂, and 3% O₂ gas mixture.10 μl of lysis buffer (saponin, triton-X, EDTA) containing a 10×solution of SYBR Green I® in RPMI media is dispensed into the plates.The plates are lidded and kept at room temperature overnight for thelysis of the infected red blood cells. The fluorescence intensity ismeasured (excitation 425 nm, emission 530 nm) using the Envision™ system(Perkin Elmer). The percentage inhibition of 50%, EC₅₀, is calculatedfor each compound.

Using the P. falciparum Proliferation Assay above, compounds of theinvention exhibit inhibitory efficacy (EC₅₀) of typically 10 μM or less,more typically less than 1 μM, most typically less than 200 nM.Compounds of the invention can significantly delay the increase in P.falciparum parasitemia. For example,3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(Example 32),N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide(Example 40),3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(Example 41),(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(Example 44),N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide(Example 53),N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide(Example 75), and3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(Example 83) all have EC₅₀ values of less than 5 nM.

The inhibitory efficacy of the compounds of the invention in delayingthe increase in P. falciparum parasitemia in infected human blood cellsis provided in Table 1.

TABLE 1 Inhibitory Efficacy of Compounds of the Invention in delaying P.falciparum Proliferation in Infected Human Blood Cells Example EC50 No.(nM) 1 8 2 342 3 94 4 46 5 88 6 284 7 975 8 532 9 6 10 7 11 6 12 9 13 814 134 15 2318 16 477 17 3 18 3 19 1 20 9 21 472 22 25 23 2 24 10 25 726 22 27 10 28 7 29 150 30 62 31 143 32 1 33 59 34 22 35 2044 36 390 37121 38 179 39 831 40 1 41 2 42 18 43 9 44 1 45 16 46 18 47 >9000 48 28849 2290 50 3850 51 60 52 13 53 1 54 9 55 32 56 8 57 4 58 30 59 228 60683 61 20 63 6 64 20 65 504 66 49 67 5 68 6750 69 13 70 4190 71 3 72 573 >10,000 74 52 75 4 76 82 77 146 79 7 80 824 81 36 82 1160 83 4 84 685 16 86 10 87 41 88 83 89 6 90 8 91 13 92 24 93 6 94 17 95 23 96 12 9713 98 19 99 1 100 9 101 6164 102 10 103 3 104 125 105 935 106 521 107 10108 2466 109 19 110 54 111 6296 112 4 113 311 114 52 115 155 116 1 117 4118 3 119 95 120 9 121 1157 122 >10,000 123 393 124 19 125 80 126 67 12749 128 4268 129 2439 130 12 131 324 132 29 133 58 134 4 135 1 137 12 13810 139 30 140 199 141 65 142 48 143 12 144 27 145 12 146 45 147 814 14867 149 4 150 51 151 67 152 228 153 88 154 200 155 82 156 210 157 91 158111 159 56 160 4 161 68 162 9 163 4 164 2 165 3Assay for Proliferation of Parasite in Infected Liver Cells

Compounds of the invention can be assayed to measure their capacity toinhibit proliferation of parasites in liver cells. The proliferation isquantified by determine the number of infected cells byimmunofluorescence.

Parasites

Due to the difficulty of successfully infecting immortalized human livercell lines with the human malaria sporozoites (liver-stage parasite),rodent malaria sporozoites from Plasmodium yoelii (17XNL) and P. berghei(ANKA) are the preferred surrogate. Sporozoites are obtained fromAnopheles stephensi mosquitoes supplied by the New York UniversityInsectary, which ships the malaria-infected mosquitoes 10-13 daysfollowing the ingestion of an infective blood meal.

Cell Line

A transgenic HepG2 cell line expressing the tetraspanin CD81 receptor(HepG2-A16-CD81^(EGFP)) is used to increase the infectivity rate ofrodent-malaria sporozoites into human cells. HepG2-A16-CD81^(EGFP) cellsare stably transformed to express a GFP-CD81 fusion protein. Acontinuous in vitro culture of this line was maintained at 37° C. in 4%CO₂ in complete media (CM) which contains: DMEM (Invitrogen, Carlsbad,USA) supplemented with 10% FCS, 0.29 mg/ml glutamine, 100 unitspenicillin and 100 μg/ml streptomycin (SigmaAldrich, USA).

Liver Stage P. yoelii Sporozoite Invasion Assay

Twenty to twenty-six hours prior to sporozoite infection, 7.5×10³HepG2-A16-CD81^(EGFP) cells are seeded into 384-well plates (Aurora 384IQ-EB black plates with clear bottoms; 50 μl of 1.5×10⁵ cells/ml in CM).These plates are incubated at 37° C. with 4% CO₂ overnight. Two hoursprior to infection, 50 nl of compound dissolved in DMSO (0.1% final DMSOconcentration per well) were transferred with a PinTool (GNF Systems)into the assay plates (10 μM final concentration). A 1:3 serial dilutionof atovaquone (10 μM at the highest final concentration) and wellstreated only with DMSO were used as positive and negative controls,respectively.

Freshly dissected salivary glands from infected mosquitoes werehomogenized in a glass tissue grinder, filtered twice through Nylon cellstrainers (40 μm pore size, BD Falcon) and counted using ahemocytometer. The assay plate with HepG2-A16-CD81^(EGFP) cells andcompound were then infected with 8×10³ sporozoitesper well and theplates are subjected to a centrifugal force of 650×g to pellet thesporozoites onto the liver cell monolayer. The assay plate is incubatedat 37° C. for 2 hours to permit sporozoite invasion, then the media isaspirated from the media plate, and replaced with 50 μl CM (containing a5× concentration of penicillin/streptomycin; 500 units penicillin and0.5 mg streptomycin per ml) per well. 50 nl of compound is re-introducedby PinTool and the assay plate incubated for 48 hours at 37° C. beforequantification of infected cells by immunofluorescence. The increasedantibiotic concentration does not interfere with the parasite orHepG2-A16-CD81^(EGFP) growth.

Atovaquone and uninfected wells were used as controls on each plate. Tworeplicate plates are tested for each assay.

After fixing the cells by addition of 12.5 μl of 20% solution ofparaformaldehyde (EMS, Hatfield, USA) to each assay well (4% finalformaldehyde concentration), membranes were permeabilized with 0.5%Triton-X-100 (Thermo Fisher Scientific) and EEFs were stained using amouse polyclonal serum raised against the Plasmodium yoelii heat shockprotein 70 (PyHSP70), a DyLight 649 goat anti-mouse IgG, Fc(gamma)fragment specific secondary antibody (Jackson Immuno Research,Cat#115-495-071) and the Hoechst 33342 nucleic acid dye (Invitrogen,Carlsbad, USA). Stained EEFs were then quantified using the OperaConfocal High Content Screening System (Perkin Elmer, Waltham, USA).Images were collected using a 20× objective lens (20×/0.45 NA, LWD PlanFluor, Olympus) at a binning of 2, using a 365 nm Xeon arc lampillumination to detect the Hoechst-labeled nuclei and 635 nm laser lineto excite DyLight649-labeled parasites. The image resolution yielded wasapproximately 0.66 μm/pixel (˜0.43 μm 2/pixel). All images were analyzedusing a custom Acapella™ (PerkinElmer) script parametrized for thisassay. In brief, images from fields inside the well were first discardedas out-of focus when the intensity in the nuclear channel was too low.Then, HepG2-A16-CD81^(EGFP) cells were counted by detecting the nucleilabeled with Hoechst using the nuclei detection libraries available withAcapella™. Parasites were later segmented using the αPyHSP70immuno-labeling signal, using a custom script library. Once the objectswere segmented from the picture, morphological-based (e.g. size,roundness, etc) and intensity-based features were measured for eachobject detected in the image (i.e. nuclei and parasites). Infectionratio was set as the ratio between parasite number and number of nucleicounted in images considered as “in-focus”. EC₅₀ values were obtainedusing parasite area and a custom curve fitting model, and a standardlogistic regression model was applied for curve fitting.

Using the P. yoelii Sporozoite Invasion Assay, compounds of theinvention exhibit inhibitory efficacy (EC₅₀) of typically 500 nM orless, more typically less than 200 nM, most typically less than 10 nM.Compounds of the invention show significantly delay of the proliferationof P. yoelii in liver cells. For exampleN-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide(Example 1),3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(Example 19),3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(Example 32),3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(Example 67), andN-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide(Example 75) all have EC₅₀ of less than 10 nM.

Inhibitory efficacy of selected compounds in delaying the proliferationof P. yoelii Sporozoite in liver cells is listed in Table 2.

Liver Stage P. berghei Luciferase Proliferation Assay

CD81-GFP-HepG2 cells (obtained from the lab of Dominique Mazier) wereseeded into GNF custom Greiner plates (1536-well, white, TC-treated,solid bottom). A final density of 3000 cells/well was achieved bydispensing 5 ul per well of a 600,000 cells/mL resuspended in AssayMedia (AM; phenol-red free DMEM, 2% FBS, 5×PSG) via a MicroFlo (Biotek;5 ul dispense cassette). The seeded assay plates were incubatedovernight at 37° C. in an incubator with 5% CO₂. The following day, a 10nL volume of compound was transferred acoustically (ECHO 525, LabcyteInc.) to each well in the assay plate. Sporozoite forms of a Plasmodiumberghei line expressing luciferase (Pb-luc) were dissected and purifiedfrom infected Anopheles stephensi mosquitoes (provided by the NYUinsectary) as previously described by Meister et al. (Science, 2011).Purified sporozoites (spz) were stored at 250 spz/uL in chilled PBSsupplemented with 3% BSA. 3 uL of Pb-luc spz solution was dispensed toeach assay well using a Bottlevalve equipped with a custom, single-tipdispense head (GNF Systems). Assay plates were centrifuged at 330×g for3 minutes to pellet the spz, then the assay plates were returned to the37° C. incubator for 48 h. Luciferase signal, which corresponds withparasite proliferation, was detected by adding 2 uL of BrightGlo(Promega) to each well using the MicroFlo (Biotek; 1 ul cassette).Luminescence was immediately measured on an Envision MultiLabel PlateReader (PerkinElmer). Wells treated with only DMSO or atovaquone (potentinhibitor of liver-stage parasites) were used for normalization of thesedata.

Using the P. berghei luciferase Proliferation Assay, four compounds,5-(5-(1-(4-cyanophenyl)-2-methylhydrazinecarbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylpicolinamide (Example 92),5-cyano-N-methyl-N-(3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide(Example 94),N-ethyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide(Example 95), andN-ethyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide(Example 96) all exhibit inhibitory efficacy (EC₅₀) of 20 nM or less.The inhibitory efficacy of the four compounds in delaying theproliferation of P. berghei Sporozoite in liver cells is listed in Table2 (identified by “*”).

TABLE 2 Inhibitory Efficacy of Compounds of the Invention by the P.yoelii Sporozoite Invasion Assay or the P. berghei luciferaseProliferation Assay Example EC₅₀ No. (nM) 1  7.3 13 17.9  19  4.3 2013.5  25 229   27 201   28 23.2  32  8.0 34 53.2  40 63.1  41 14.3  5479  67  4.6 75   2.25 90 39  91 23  92 15* 93 10  94 13* 95  5* 96  4*97 92  98 2063   99 15  100 20  102 660  103 62  104 1200   107 180  108472  109 62  110 253  111 >10,000     112 9 113 1649   114 950  115 79 116 3 117 7 118 1 119 56  133 34* 136 10* 137 10* 140 84  141 17* 143 7* 144 22* 145  8* 146 20* 147 151*  148 18* 149  1* 150 19* 151  7*152 182*  153 16* 154 36* 155 21* 156 54* 157 60* 158 11* 159 43* 160 4* 161 41* 162  8* 163  2* *analyzed by the P. berghei luciferaseProliferation Assay

Preparation of the Compounds of the Invention

The present invention also includes processes for the preparation ofcompounds of the invention. In the reactions described, it can benecessary to protect reactive functional groups, for example hydroxy,amino, imino, thio or carboxy groups, where these are desired in thefinal product, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Synthesis”, John Wiley and Sons, 1991.

Typically, the compounds of formula (I) can be prepared according tosynthetic routes 1-6 provided infra., where Ring A, Ring C, R₁, R₂, R₁₇,n and p are as defined in the Summary of the Invention. The followingreaction schemes are given to be illustrative, not limiting,descriptions of the synthesis of compounds of the invention. Detaileddescriptions of the synthesis of compounds of the invention are given inthe Examples, infra.

General Synthetic Route I

Reaction Conditions:

-   -   a. mild heating in a polar, aprotic solvent such as DMF, NMP,        DMA or DMSO;    -   b. base such as K₂CO₃ or Na₂CO₃ in a polar organic solvent such        as DMF, NMP or DMSO;    -   c. esters can be hydrolyzed under conventional acidic or basic        conditions; decarboxylation occurs when the di-acid is heated at        50-100° C.;    -   d. esterification can be done in alcohol (MeOH, EtOH) using acid        catalysis (AcCl or TMSCl to generate HCl, or catalytic H₂SO₄ or        toluene sulfonic acid, for example);    -   e. N-bromosuccinimide (NBS) or similar brominating agent in        CH₂Cl₂, CHCl₃ or CCl₄ at −78° C. to room temperature;    -   f. conventional base-catalyzed hydrolysis in aqueous alcohol        solvent;    -   g. the carboxylic acid can be activated by various known        methods, e.g., forming an acid chloride using oxalyl chloride or        thionyl chloride and DMF followed by acylation of an amine of        formula

-   -    in a non-reactive solvent using an amine base such as Et₃N,        DIEA (Hunig's base) or DMAP (dimethylaminopyridine). Various        amide coupling reagents such as dicyclohexyl carbodiimide can        also be used; and    -   h. Pd-catalyzed Suzuki coupling.        General Synthetic Route 2

Reaction Conditions:

-   -   a. mild heating in a polar, aprotic solvent such as DMF, NMP,        DMA or DMSO;    -   b. base such as K₂CO₃ or Na₂CO₃ in a polar organic solvent such        as DMF, NMP or DMSO;    -   c. conventional base-catalyzed hydrolysis in aqueous alcohol        solvent.

Ring C can then be added using known methods, such as amide formation tolink the carboxylic acid with an amine of formula

General Synthetic Route 3

Reaction Conditions:

-   -   a. Curtius rearrangement of carboxylic acid using diphenyl        phosphoryl azide, t-butyl alcohol and an appropriate base.    -   b. optionally exchanged hydrogen on the carbamate with an R₂        group by reacting with and R₂X group where X is a leaving group        (such as Cl), in basic DMF at room temperature or lightly        elevated temperature for a few hours;    -   c. Acidic cleavage of t-butyl carbamate    -   d. acylation with acid chlorides in        dichloromethane/triethylamine at room temperature.        General Synthetic Route 4

Ring A may be added by known methods such as the Suzuki couplingillustrated in Synthetic Route 1.

General Synthetic Route 5

The amine intermediate (Step c of Synthetic Route 3) may be alkylatedwith the Ring C moiety (where X is a leaving group, such as Cl, Br or I,or a sulfonate ester such as MeSO₃-TsO—, and the like) in an organicsolvent, with a catalytic amount of DMAP and a non-nucleophilic base, at0° C. to mild heating. Typical organic solvent includes halogenatedsolvents like DCM or CHCl₃; ether solvents such as THF, dioxane, MTBE,diethyl ether. Typical non-nucleophilic base includes triethylamine,diisopropyl ethylamine, potassium t-butoxide, potassium carbonate, andthe like.

General Synthetic Route 6

Ring A may be then added by known methods such as the Suzuki couplingillustrated in Synthetic Route I.

General Procedures for Boronic Ester Synthesis

Boronic Ester Synthesis Procedure A: PdCl₂(dppf)-CH₂Cl₂;

A mixture of bromo compound (1.0 eq.) and bis(pinacolato)diboron (1.1eq.) and potassium acetate (2.0 eq.) dissolved in 1,4-dioxane (10 vol)was degassed with argon gas for 15 min. Subsequently, PdCl₂(dppf).CH₂Cl₂(0.05 eq.) was added and the reaction mixture was stirred at 85-100° C.for 16 h. The reaction mixture (generally black color) was filtered andconcentrated under reduced pressure. The resulting black mixture wasused further without any purification.

Boronic Ester Synthesis Procedure B: Pd(PPh₃)₄;

A mixture of bromo compound (1.0 eq.) and bis(pinacolato)diboron (1.1eq.), and potassium acetate (2.0 eq.) dissolved in 1,4-dioxane (10 vol)was degassed with argon gas for 15 min. Subsequently, Pd₂(dba)₃ (0.05eq.) and tricyclohexyl phosphine (0.05 eq.) were added and the reactionmixture was stirred at 90-110° C. for 16 h. The reaction mixture(generally black color) was filtered and concentrated under reducedpressure. The crude product was used further without any purification.

General Procedures for Suzuki Couplings

Suzuki Procedure A: SiliaCat® DPP-Pd and K₂CO₃:

A mixture of bromo compound (51 mg, 0.2 mmol, 1.0 equiv.), boronic acid(0.22 mmol, 1.1 equiv.), and SiliaCat® DPP-Pd (0.25 mmol/g loading, 34mg, 0.01 mmol, 0.05 equiv.) was treated with 660 μL dioxane and 220 μL 1M aq. K₂CO₃ and the resulting mixture was allowed to heat overnight at100° C. in a capped vial. The resulting black mixture was dry-loadedonto silica gel and was purified by silica gel chromatography, elutingwith hexanes/EtOAc to give the desired product.

Suzuki Procedure B: Pd(Dppf)Cl2 and K₂CO₃ in the Microwave:

A mixture of aryl bromide (1.0 equiv.), aryl boronic acid (1.5 equiv.),K₂CO₃ (2.5 equiv.), and Pd(dppf)Cl₂ (0.05-0.15 equiv.) in THF/water wasallowed to heat at 140° C. in a microwave reactor for 40 minutes.Purified by mass-triggered HPLC or silica gel chromatography to providethe desired product.

Suzuki Procedure C: SiliaCat® DPP-Pd/Pd(Dppf)Cl₂ and K₂HPO₄ in theMicrowave:

A mixture of aryl bromide (1.0 equiv.), aryl boronic acid (1.5 equiv.),KH₂PO₄ (3.5 equiv.), and SiliaCat® DPP-Pd or Pd(dppf)Cl₂ (0.05-0.15equiv.) in THF/water was allowed to heat at 150° C. in a microwavereactor for 40-60 minutes. Purified by mass-triggered HPLC or silica gelchromatography to provide the desired product.

Suzuki Procedure D: Pd(Dppf)Cl₂, K₂CO₃, DME-WATER:

A mixture of aryl bromide (1.0 equiv.), aryl boronic acid (1.5 equiv.),K₂CO₃ (3.0 equiv.), and Pd(dppf)Cl₂ (0.05-0.15 equiv.) in DME/water wasallowed to heat at 110° C. for two hours. Following extraction of thereaction mixture with CH₂Cl₂, the combined organic extracts wereconcentrated and the residue was purified by silica gel chromatography,eluting with hexanes/EtOAc to give the desired product.

Suzuki Procedure E: Pd₂(Dba)₃, P(O-Tolyl)₃, 2M KF Solution inToluene/Ethanol:

A mixture of aryl bromide (1.0 equiv.), aryl boronic acid (1.2-2.0equiv.), 2 M aq KF (3 equiv.), and Pd₂(dba)₃ (0.1 equiv.), P(o-tolyl)₃(0.1 equiv.) in toluene:ethanol (7:3) was degassed and heated to 100° C.for 1-5 h. The crude products were purified by preparative TLC or silicagel chromatography to provide the desired product.

Suzuki Procedure F: Pd(PPh₃)₄, 1N Na₂CO₃, Dioxane:

A mixture of aryl bromide (1.0 equiv.), aryl boronic acid (1.2-2.0equiv.), 1 N Na₂CO₃ (2.0 equiv.), and Pd(PPh₃)₄ (0.2 equiv.) in1,4-dioxane was degassed and heated in a sealed tube to 100° C.(microwave or conventional heating) for 2-6 h. The crude products werepurified by preparative TLC or silica gel chromatography to provide thedesired product.

Suzuki Procedure G:

A solution mixture of bromo compound (1.0 equivalent), boronic acid (1.3equiv) and aq. 1N Na₂CO₃ (2.0 equivalent) in 1,4-dioxane (0.1 M) takenin a sealed tube was degassed with argon for about 20 min. Pd(PPh₃)₄(0.1 equivalent) was added under argon atmosphere. The resultingreaction mixture was stirred at 90-100° C. for 2-16 h. The reactionmixture cooled to room temperature and filtered through celite. Thefilterate was taken in to water and ethyl acetate. The ethyl acetatelayer was washed with water, brine, dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by silica (100-200 mesh)column chromatography using a solvent gradient of 1-2% methanol inchloroform as eluant. Some instances compounds were further purified byprep-TLC or prep-HPLC to obtain as yellow solids.

Suzuki Procedure H:

A solution mixture of bromo compound (1.0 equivalent), boronic acid (1.3equivalent) and aq. 2M KF solution (3.0 equivalent) in toluene:ethanol(7:3) (0.1 M) was degassed with argon for about 15 min. Pd₂(dba)₃ (0.1equivalent) and P(o-tolyl)₃ (0.1 equivalent) were added under argonatmosphere. The resulting reaction mixture was maintained at 100° C. for2-16 h. The reaction mixture was allowed to room temperature andfiltered through celite. The filtrate was partitioned between water andethyl acetate. The ethyl acetate layer was washed with brine, dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The crudecompound was purified by column chromatography over silica gel (100-200mesh) using a solvent gradient of 1-2% methanol in chloroform as eluantto obtain product.

Suzuki Procedure I:

A solution mixture of bromo compound (1.0 equivalent), boronic acid (1.5equivalent) and NaHCO₃ (2.5 equivalent) in acetonitrile:water (9:1) (0.1M) was degassed with argon for about 30 min. Pd₂(dba)₃.CHCl₃ adduct (0.1equivalent) and X-phos (0.1 equivalent) were added under argonatmosphere. The resulting reaction mixture was maintained at 100° C. for2 h and allowed it to room temperature and filtered through celite. Thefiltrate was partitioned between water and ethyl acetate. The ethylacetate layer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyover silica gel (100-200 mesh) using a solvent gradient of 80-100% of EAin cyclohexane or 1-2% methanol in dichloromethane as eluant to obtainproducts as yellow solids. This solids on re-precipitation fromdichloromethane-pentane mixture afforded pure compounds.

General Procedures of Amide Coupling

Amide Coupling Method 1:

To a solution of carboxylic acid (1.0 equivalent) in dichloromethane(0.2 M) was added oxalyl chloride (2.8 equivalent) followed by catalyticamount of N,N-dimethylformamide at room temperature and stirred for0.5-2 h. The resultant volatiles were distilled-off under reducedpressure to afford crude acid chloride. The acid chloride indichloromethane (0.2 M) was added to corresponding amine (1.0equivalent) and DIPEA (2.8 equivalent) in dichloromethane (1 M) at 0° C.The resulting reaction mixture was stirred at room temperature for 1h-16 h. The reaction mixture was diluted with dichloromethane (50 mL).The organic layer was washed with 1N HCl, sat. NaHCO₃, water, brine,dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. Thecrude product was purified by column chromatography over silica gel(100-200 mesh) using a solvent gradient of 25%-100% of ethyl acetate inpet-ether.

Amide Coupling Method 2:

A solution mixture of acid (1.0 equivalent), amine (3.0 equivalent),HATU (1.0 equivalent), and DIPEA (3.0 equivalent) in dry THF (0.1 M) wasstirred at room temperature for 16 h. The volatiles were distilled offunder reduced pressure, the residue was dilute with water and extractedwith ethyl acetate. The combined extracts were washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The crude compound was purifiedby column chromatography over silica-gel (100-200 mesh) using a solventgradient of ethyl acetate in chloroform as eluant.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure material.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

The present invention is further exemplified, but not to be limited, bythe following examples and intermediates that illustrate the preparationof compounds of the invention. It is understood that if there appears tobe a discrepancy between the name and structure of a particularcompound, the structure is to be considered correct as the compoundnames were generated from the structures.

Temperatures are given in degrees Celsius. If not mentioned otherwise,all evaporations are performed under reduced pressure, typically betweenabout 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis and spectroscopiccharacteristics, e.g., MS, IR, NMR. Abbreviations used are thoseconventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

LC-MS Methods

Method 1:

Waters Acquity Binary Gradient Pump; Waters Acquity PDA Detector. WatersAuto sampler; Waters Quattro micro API Mass Spectrometer with ESI andAPCI ion source; UPLC Column: Waters Acquity; BEH; C18 1.7 um 50×2.1 mm;Mobile Phase: (A) H₂O+0.025% TFA and (B) Acetonitrile+0.025% TFA.Gradient: 0.4 mL/minute, initial 15% B ramp to 95% B over 3.0 minutes,then hold until 4.0 minutes, return to 15% B at 4.1 minutes until end ofrun, then equilibrated the column for 2.0 minutes; MS Scan: 100 to 1000amu in 0.5 seconds per channel; Diode Array Detector: 200 nm and 400 nm.

Method 2:

Waters Acquity Binary Gradient Pump; Waters Acquity PDA Detector. WatersAuto sampler; Waters Quattro micro API Mass Spectrometer with ESI andAPCI ion source; UPLC Column: Waters Acquity; BEH; C18 1.7 um 50×2.1 mm;Mobile Phase: (A) H₂O+0.025% TFA and (B) Acetonitrile+0.025% TFA.Gradient: 0.4 mL/minute, initial 20% B ramp to 90% B over 2.0 minutes,then hold until 4.0 minutes, return to 20% B at 4.1 minutes until end ofrun, then equilibrated the column for 2.0 minutes; MS Scan: 100 to 1000amu in 0.5 seconds per channel; Diode Array Detector: 200 nm and 400 nm.

Method 3:

Waters Acquity Binary Gradient Pump; Waters Acquity PDA Detector. WatersAuto sampler; Waters Acquity Evaporative Light Scattering Detector;Waters Quattro micro API Mass Spectrometer with ESI and APCI ion source;UPLC Column: Waters Acquity; BEH; C18 1.7 um 100×2.1 mm; Mobile Phase:(A) H₂O+0.025% TFA and (B) Acetonitrile+0.025% TFA. Gradient: 0.3mL/minute, initial 10% B ramp to 80% B over 4.0 minutes, then hold until6.0 minutes, return to 10% B at 6.1 minutes until end of run, thenequilibrated the column for 2.5 minutes; MS Scan: 100 to 1000 amu in 0.5seconds per channel; Diode Array Detector: 200 nm and 400 nm; Drift tubetemperature: 50° C. and N2 gas flow: 40 Psi for ELSD Detector.

Method 4:

Waters Acquity Binary Gradient Pump; Waters Acquity PDA Detector. WatersAuto sampler; Waters Quattro micro API Mass Spectrometer with ESI andAPCI ion source; UPLC Column: Waters Acquity; BEH; C18 1.7 um 50×2.1 mm;Mobile Phase: (A) H₂O+0.025% TFA and (B) Acetonitrile+0.025% TFA.Gradient: 0.4 mL/minute, initial 20% B ramp to 80% B over 2.0 minutes,then hold until 4.0 minutes, return to 20% B at 4.1 minutes until end ofrun, then equilibrated the column for 2.0 minutes; MS Scan: 100 to 1000amu in 0.5 seconds per channel; Diode Array Detector: 200 nm and 400 nm

Method 5:

Waters Acquity Binary Gradient Pump; Waters Acquity PDA Detector. WatersAuto sampler; Waters Quattro micro API Mass Spectrometer with ESI andAPCI ion source; UPLC Column: Waters Acquity; BEH; C18 1.7 um 50×2.1 mm;Mobile Phase: (A) H₂O+0.025% TFA and (B) Acetonitrile+0.025% TFA.Gradient: 0.4 mL/minute, initial 10% B ramp to 80% B over 3.0 minutes,then hold until 4.0 minutes, return to 20% B at 4.1 minutes until end ofrun, then equilibrated the column for 2.0 minutes; MS Scan: 100 to 1000amu in 0.5 seconds per channel; Diode Array Detector: 200 nm and 400 nm

Method 6:

Agilent G1379A Degasser; Agilent G1312A Binary Pump; Agilent G1315CDiode Array Detector; Agilent G1367A Auto sampler; Agilent Ion Trap MassSpectrometer with ESI source; HPLC Column: Waters X-Terra; MS; C18; 2.5um 50×4.6 mm; Mobile Phase: (A) 0.01 M Ammonium Bicarbonate in Water and(B) Acetonitrile; Gradient: 1 mL/minute, initial 50% B, ramp to 80% Bover 4.0 minutes, and hold until 6.0 minutes, return to 50% B at 6.1minutes until end of run. The column is re-equilibrated for 3 minutes.MS Scan: 100 to 1200 amu; Diode Array Detector: 200 nm-400 nm.

Method 7:

Agilent G1379A Degasser; Agilent G1312A Binary Pump; Agilent G1315CDiode Array Detector; Agilent G1367A Auto sampler; Agilent Ion Trap MassSpectrometer with ESI source; HPLC Column: Waters X-Bridge; C18; 3.5 um150×4.6 mm; Mobile Phase: (A) 0.01 M Ammonium Bicarbonate in Water and(B) Acetonitrile; Gradient: 1 mL/minute, initial 20% B, ramp to 80% Bover 4.0 minutes, and hold until 8.0 minutes, return to 20% B at 8.1minutes until end of run. The column is re-equilibrated for 3 minutes.MS Scan: 100 to 1200 amu; Diode Array Detector: 200 nm-400 nm.

Method 8:

Agilent G1379A Degasser; Agilent G1312A Binary Pump; Agilent G1315CDiode Array Detector; Agilent G1367A Auto sampler; Agilent Ion Trap MassSpectrometer with ESI source; HPLC Column: Waters Symmetry; C18; 3.5 um75×4.6 mm; Mobile Phase: (A) H₂O+0.1% Formic acid and (B)Acetonitrile+0.1% Formic acid; Gradient: 1 mL/minute, initial 20% B,ramp to 80% B over 4.0 minutes, and hold until 7.0 minutes, return to20% B at 7.1 minutes until end of run. The column is re-equilibrated for3 minutes. MS Scan: 100 to 1200 amu; Diode Array Detector: 200 nm-400nm.

EXAMPLES Intermediate I-1 Methyl3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxylate

To a solution of methyl isonicotinate (500 μL, 4.23 mmol, 1.0 equiv.) in2 mL DMF was added O-(2,4-dinitrophenyl)hydroxylamine (1 g, 5.02 mmol,1.2 equiv.) and the resulting solution was allowed to stir overnight at40° C., during which time the reaction became heterogeneous. The mixturewas allowed to cool to rt before being diluted with 10 mL DMF, thentreated with 4-ethynyl-α,α,α-trifluorotoluene (863 μL, 5.29 mmol, 1.25equiv.) and potassium carbonate (877 mg, 6.35 mmol, 1.5 equiv.). Themixture was allowed to stir overnight at 100° C. The resulting mixturewas allowed to cool to rt, and then the solvent was removed underreduced pressure. The residue was diluted with water and the aqueouslayer was extracted with EtOAc five times. The combined EtOAc extractswere washed once with water, once with brine, and then dried with MgSO₄,filtered, and the solvent removed under reduced pressure. The materialwas purified by silica gel chromatography, eluting with hexanes/EtOAc(Rf=0.26 in 5:1 hexanes/EtOAc) to give 335 mg (25% yield) I-1. ¹H NMR(400 MHz, CDCl₃, δ): 8.52 (m, 2H), 8.23 (s, 1H), 7.72 (s, 4H), 7.40 (dd,J=1.59, 7.50 Hz, 1H), 3.96 (s, 3H).

Intermediate I-23-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxylic acid

A solution of ester (320 mg, 1 mmol, 1.0 equiv.) in 3 mL 1:1MeOH-dioxane was treated with 1 N aq. NaOH (1.5 mL, 1.5 mmol, 1.5equiv.) dropwise over a few minutes, during which time the reactionbecame heterogeneous. The thick mixture was allowed to stir well at roomtemperature until complete (approximately three hours). As the reactionprogressed, it became homogeneous. The resulting solution was dilutedwith 6 mL water, then was treated with 1 N aq. HCl (1.5 mL, 1.5 mmol,1.5 equiv.) dropwise over a few minutes and allowed to stir well severalminutes more to break up any clumps. The mixture was filtered and thefilter cake was rinsed with water, followed by hexanes. The solid wasdried under high vacuum overnight to provide I-2 (quant.).

Intermediate I-3 3-ethyl 5-methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylate

To a solution of methyl isonicotinate (500 μL, 4.23 mmol, 1.0 equiv.) in2 mL DMF was added O-(2,4-dinitrophenyl)hydroxylamine (1 g, 5.02 mmol,1.2 equiv.) and the solution was allowed to stir overnight at 40° C.,during which time the reaction became heterogeneous. The mixture wasallowed to cool to room temperature before being diluted with 10 mL DMF,then treated with ethyl propiolate (536 μL, 5.29 mmol, 1.25 equiv.) andpotassium carbonate (877 mg, 6.35 mmol, 1.5 equiv.). The mixture wasallowed to stir overnight at rt. After the solvent was removed underreduced pressure, the residue was diluted with water and the aqueouslayer was extracted with EtOAc five times. The combined EtOAc extractswere washed once with water and once with brine, then dried with MgSO₄,filtered, and the solvent was removed under reduced pressure. Thematerial was purified by silica gel chromatography, eluting withhexanes/EtOAc to give 778 mg (74% yield) of I-3. ¹H NMR (400 MHz, CDCl₃)δ 8.86 (dd, J=0.9, 1.8, 1H), 8.55 (dd, J=0.9, 7.2, 1H), 8.47 (s, 1H),7.52 (dd, J=1.8, 7.2, 1H), 4.42 (q, J=7.1, 2H), 3.99 (s, 3H), 1.44 (t,J=7.1, 3H).

Intermediate I-4 Pyrazolo[1,5-a]pyridine-5-carboxylic acid

A suspension of diester (8.5 g, 34.2 mmol, 1.0 equiv.) in 150 mL 40%H₂SO₄ was allowed to heat at 100° C. overnight in a septum-capped vialfitted with a needle outlet to an empty balloon to accommodate the gasevolution. The resulting solution was allowed to cool to rt, then placedin a cold water bath before bringing to approx. pH=2 with NaOH. Duringthis pH adjustment, the acid precipitated and was isolated byfiltration. The solid was washed with water, and then dried under highvacuum overnight to provide acid I-4. ¹H NMR (400 MHz, DMSO) δ 12.5 (brs, 1H), 8.74 (d, J=7.3, 1H), 8.34 (m, 1H), 8.11 (d, J=2.3, 1H), 7.25(dd, J=1.9, 7.3, 1H), 6.89 (dd, J=0.8, 2.3, 1H).

Intermediate I-5 Methyl pyrazolo[1,5-a]pyridine-5-carboxylate

A solution of acid (200 mg, 1.23 mmol, 1.0 equiv.) in 3.7 mL MeOH wasallowed to cool to 0° C., then AcCl (370 μL) was added dropwise withefficient stirring. The resulting solution was allowed to warm to rt,then allowed to heat at 65° C. overnight in a sealed vial. The resultingsolution was allowed to cool to rt before the solvent was evaporated.The residue was diluted with EtOAc, and then washed with saturated aq.NaHCO₃ and brine, dried with MgSO₄, filtered, and the solvent wasremoved under reduced pressure to give 110 mg of the desired ester I-5,which was taken on without further purification.

Intermediate I-6 Methyl 3-bromopyrazolo[1,5-a]pyridine-5-carboxylate

A solution ester (110 mg, 0.62 mmol, 1.0 equiv.) in 6.3 mL CH₂Cl₂ wasallowed to cool to −78° C., then NBS (110 mg, 0.62 mmol, 1.0 equiv.) wasadded in one portion. The resulting mixture was allowed to warm to rtand then stir at that temperature for one hour. The solvent was removedunder reduced pressure and the resulting material was purified by silicagel chromatography, eluting with hexanes/EtOAc to give I-6. ¹H NMR (400MHz, CDCl₃, δ): 8.43 (dd, J=0.80, 7.28, 1H), 8.27 (m, 1H), 7.99 (s, 1H),7.36 (dd, J=1.83, 7.30 Hz, 1H), 3.96 (s, 3H).

Intermediate I-7 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic acid

A solution of ester (195 mg, 0.764 mmol, 1.0 equiv.) in 4 mL MeOH wastreated with 1 N aq. NaOH (2 mL, 2.0 mmol, 2.6 equiv.) at rt, and thenallowed to stir at rt for one hour. Concentrated under reduced pressure,then diluted with water and acidified with 4 N aq. HCl. Extracted 3×10mL EtOAc, dried the combined organic extracts with Na₂SO₄, filtered andthe solvent removed under reduced pressure to give the desired acid I-7,which was taken on without further purification.

Intermediate I-83-bromo-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

A solution of acid (1.0 equiv.) in CH₂Cl₂ (˜0.05-0.1 M) was treated withoxalyl chloride (2.0-3.0 equiv.) and a catalytic amount of DMF. Theresulting solution was allowed to stir at rt for between five minutesand one hour, then was concentrated and dried briefly under high vacuum.The resulting acid chloride was diluted with CH₂Cl₂ (˜0.05-0.1 M), andto this solution was added 4-cyano-N-methylaniline (1.1-3.0 equiv.) andeither DIEA or Et3N (3.0 equiv.). The resulting mixture was allowed tostir at room temperature until complete conversion (generally less thanthree hours). The solvent was removed under reduced pressure, and theresidue was purified by silica gel chromatography.

Intermediate I-93-bromo-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-9 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile with 6-(methylamino)nicotinonitrile.

Alternatively, I-9 was prepared using the general procedure of amidecoupling-Method 1. Yield 45%. White solid. ¹H NMR (400 MHz, CDCl₃): δ8.68 (s, 1H), 8.35 (d, J=6.83 Hz, 1H), 7.99 (s, 1H), 7.82 (dd, J=1.9,7.7 Hz, 1H), 7.68 (s, 1H), 7.37 (d, J=8.8 Hz, 1H), 6.73-6.75 (m, 1H),3.64 (s, 3H).

Intermediate I-103-bromo-N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-10 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile withN-methyl-5-(methylsulfonyl)pyridin-2-amine.

Intermediate I-113-bromo-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-11 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile withN-methyl-5-(trifluoromethyl)pyridin-2-amine.

Intermediate I-123-bromo-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-12 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile with N,5-dimethylpyridin-2-amine.

Intermediate I-133-bromo-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(Example 64)

Intermediate I-13 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile with 4-fluoro-N-methylaniline. ¹H NMR (400MHz, METHANOL-d₄) δ 3.49 (s, 3H) 6.80 (d, J=7.53 Hz, 1H) 7.00-7.14 (m,2H) 7.24-7.37 (m, 2H) 7.50 (s, 1H) 7.97 (s, 1H) 8.38 (d, J=7.28 Hz, 1H);ESI-LC/MS (m/z): [M−H]⁺ 349.

Intermediate I-143-bromo-N-(4-chloro-2-formylphenyl)-N-methylimidazo[1,2-a]pyrazine-6-carboxamide

Intermediate I-14 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile with 5-chloro-2-(methylamino)benz-aldehyde.¹H NMR (400 MHz, CDCL₃) δ 10.21 (s, 1H), 8.77 (s, 1H), 8.45-8.48 (m,1H), 7.77-7.84 (m, 2H), 7.44-7.46 (m, 2H), 7.09-7.11 (m, 1H), 3.52 (s,3H); ESI-LC/MS (Method 1) (m/z): [M+H]⁺ 392.89 [M+2H]⁺ 394.90 & [M+4H]⁺396.92.

Intermediate I-153-bromo-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-15 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile with 5-chloro-2-(methylamino)benz-aldehyde.¹H NMR (400 MHz, CDCL₃) δ 10.04 (s, 1H), 8.18-8.28 (m, 1H) 7.90-7.95 (m,1H) 7.77 (s, 1H) 7.57-7.61 (m, 1H) 7.40 (s, 1H) 6.61 (br. s, 1H) 3.49(s, 3H); ESI-LC/MS (Method 1) (m/z): [M+H]⁺ 391.94 & [M+2H]⁺ 393.89 &[M+4H]⁺ 395.91.

Intermediate I-163-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of aryl bromide (1.0 equiv.), aryl boronic acid (1.5 equiv.),K₂CO₃ (2.5 equiv.), and Pd(dppf)Cl₂ (0.05-0.15 equiv.) in THF/water wasallowed to heat at 140° C. in a microwave reactor for 40 minutes. Theresulting mixture was concentrated under reduced pressure and purifiedby silica gel chromatography to give I-16.

Intermediate I-17 3-bromo-5-ethylpyrazolo[1,5-a]pyridine

To a stirred solution of 5-ethylpyrazolo[1,5-a]pyridine (1.1 g, 0.008mmol) in dichloromethane (10 mL) at 0° C. was added NBS (1.75 g, 0.009mmol) and reaction mixture was stirred at room temperature for 5 min.Subsequently, water was added and the reaction mixture was extractedwith dichloromethane (2×10 mL). The organic layer was washed with water(1×30 mL), sat. NaHCO₃ solution (1×10 mL), brine (1×10 mL), dried overNa₂SO₄ and concentrated to afford 2.1 g (84%) of3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17) as a brownish highlyviscous liquid. The crude was progressed to next step without anyfurther purification. ESI-LC/MS (m/z): [M+H]⁺ 225.0, [(M+2)+H]⁺ 227.0,RT 2.50 min.

Intermediate I-18 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine

To a stirred solution of 3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17,2.1 g, 0.0094 mmol) in CCl₄ (20 mL) at rt was added NBS (2 g, 0.01 mmol)followed by benzoyl peroxide (1.1 g, 0.004 mmol). The resulting reactionmixture was heated to 77° C. After 2 h, the reaction mixture was allowedto cool to rt and subsequently water (20 mL) was added followed byextraction with dichloromethane (2×20 mL). The combined organic layerswere washed with water (1×20 mL), sat NaHCO₃ solution (1×10 mL), brine(1×10 mL), dried over Na₂SO₄ and the solvent was removed under reducedpressure. The resulting crude product was purified by columnchromatography over silica gel (petroleum ether/EtOAc, 0-5% EtOAc) toafford 820 mg (29%) of 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine(I-18) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=7.91 Hz,1H), 7.93 (s, 1H), 7.46 (d, J=1.32 Hz, 1H), 6.90-6.92 (dd, J=1.76, 5.71Hz, 1H), 5.19-5.24 (m, 2H), 2.08 (d, J=7.04 Hz, 3H); ESI-LC/MS (m/z):[M+H]⁺ 302.9, [(M+2)+H]⁺ 304.9, [(M+4)+H]⁺ 306.9, RT 2.65 min

Intermediate I-19N-(1-(3-bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-N,5-dimethylpyridin-2-amine

A suspension of 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18,400 mg, 1.32 mmol), N,5-dimethylpyridin-2-amine (230 mg, 1.98 mmol) andK₂CO₃ (546 mg, 3.96 mmol) in acetonitrile was heated to 90° C. in asealed tube for overnight. The reaction mixture was cooled to roomtemperature and water (10 mL) was added. The aqueous phase was extractedwith ethyl acetate (2×10 mL). The combined organic layers were driedover Na₂SO₄ and solvents were removed under reduced pressure. Theresulting crude product was purified by column chromatography oversilica gel (petroleum ether/EtOAc, 0-4% EtOAc) to afford 210 mg (46%) ofN-(1-(3-bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-N,5-dimethylpyridin-2-amine(I-19) as a yellow solid. ESI-LC/MS (m/z): [M+H]⁺ 345.2, [(M+2)+H]⁺ 347,RT 3.31 min.

Intermediate I-20(3-bromopyrazolo[1,5-a]pyridin-5-yl)(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone

To a solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic acid (I-7,250 mg, 1.040 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.25 mL), followed by catalytic amount DMF (0.1 M) at rt and themixture was stirred for 30 min. The resultant volatiles were removedunder reduced pressure to afford a residue of acid chloride. To thisresidue was added 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (191 mg,1.25 mmol) in dichloromethane (10.0 mL), followed by DIPEA (0.5 mL) andthe mixture was stirred at rt for 30 min. The reaction mixture wasdiluted with dichloromethane (50 mL).

The reaction mixture was washed with 1N HCl, sat. NaHCO₃ solution,water, brine, dried over Na₂SO₄, and the solvent was removed underreduced pressure to afford 300 mg (77%) of(3-bromopyrazolo[1,5-a]pyridin-5-yl)(7-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone(I-20) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J=7.68 Hz,1H), 8.27 (s, 1H), 7.80 (s, 1H), 7.06 (d, J=6.7 Hz, 1H), 6.84 (d, J=10.3Hz, 1H), 6.65-6.68 (m, 1H), 6.50-6.52 (m, 1H), 4.36 (m, 2H), 3.92 (m,2H); ESI-LC/MS (m/z): [M+H]⁺ 376.0, [(M+2)+H]⁺ 378.0, RT 2.37 min.

Intermediate I-21 2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide

To a solution of 2-amino-5-fluorophenol (1.0 g, 7.87 mmol) indichloromethane (50 mL) at 0° C. was added 2-Chloroacetyl chloride (978mg, 8.66 mmol). The reaction mixture was stirred at rt for 2 h, followedby addition of aqueous saturated NaOH solution. The organic layer waswashed with brine, dried over Na₂SO₄ and solvent was removed underreduced pressure to afford 550 mg (35%) of2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide (I-21) as a brown solid.ESI-LC/MS (m/z): (M−H)⁻ 201.6, RT 2.65 min.

Intermediate I-22 7-fluoro-4a,5-dihydro-2H-benzo[b][1,4]oxazin-3(4H)-one

To a solution of 2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide (5.5 g,27 mmol) in acetonitrile (40 mL) was added DIPEA (7 g, 54 mmol) and thereaction solution was stirred at 80° C. for 2 h. The solvent was removedunder reduced pressure and the residue was partitioned betweendichloromethane (50 mL) and water (50 mL). The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure toafford 3.5 g (78%) of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one as abrown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (br. s, 1H) 6.67-6.77 (m,3H) 4.62 (s, 2H).

Intermediate I-23 7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a stirred solution of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one(I-22, 1 g, 5.98 mmol) in THF (25 mL) at 0° C. was added 3M CH₃MgBr (8mL, 24 mmol). After addition, the cooling bath was removed and themixture was heated to 65° C. for 4 h. The reaction mixture was quenchedwith acetic acid (10 mL) at 0° C. and NaBH₄ (568 mg, 15 mmol) was addedto the solution. The resulting solution was stirred at rt for overnight.Subsequently, 3N aqueous NaOH solution was cautiously added until pHvalue of the mixture was adjusted to 10.0. The basic solution wasextracted with ethyl acetate (2×30 mL). The combined organic layers werewashed with water, brine, dried over Na₂SO₄ and the solvent was removedunder reduced pressure. The resulting crude product was purified bycolumn chromatography over neutral alumina (petroleum ether/EtOAc, 0-15%EtOAc) to afford 135 mg (14%) of7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (I-23) as a brownoil. ¹H NMR (400 MHz, DMSO) δ 6.45-6.55 (m, 3H), 4.16-4.19 (m, 1H),3.73-3.77 (m, 1H), 3.44-3.51 (m, 2H), 1.17 (d, J=6.34 Hz, 3H).

Intermediate I-24(3-bromopyrazolo[1,5-a]pyridin-5-yl)(7-fluoro-3-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)methanone

Intermediate I-24 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile with7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (I-23, 350 mg, 2.1mmol). The resulting crude product was purified by column chromatographyover silica gel (chloroform/EtOAc, 0-30% EtOAc) to afford 150 mg (20%)of(3-bromopyrazolo[1,5-a]pyridin-5-yl)(7-fluoro-3-methyl-2H-benzo[b][1,4]oxazin-4(3H)-yl)-methanone(I-24) as an off-white solid. ¹H NMR (400 MHz, DMSO) δ ¹H NMR (400 MHz,CDCl₃) δ 8.36 (d, J=7.0 Hz, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 6.88 (br.s, 1H), 6.67-6.78 (m, 3H), 6.42-6.46 (m, 1H), 4.82 (br. s, 1H),4.28-4.35 (m, 2H), 1.33 (d, J=7.0 Hz, 3H).

Intermediate I-25 6-(oxetan-3-ylamino)nicotinonitrile

In a microwave vial, oxetan-3-amine (125 mg, 1.736 mmol), triethylamine(526 mg, 5.21 mmol) were added to a solution of 2-bromo-5-cyanopyridine(317 mg, 1.736 mmol) in isopropanol (3 mL). The vial was capped andirradiated in a microwave oven at 120° C. for 5 h. The reaction mixturewas partitioned between ethyl acetate (10 mL) and water (10 mL). Theorganic layer was washed with brine, dried over Na₂SO₄ and the solventwas removed under reduced pressure. The resulting crude product waspurified by column chromatography over silica gel (chloroform/MeOH, 0-5%EtOAc) to afford 75 mg (25%) of 6-(oxetan-3-ylamino)nicotinonitrile(I-25) as an off-white solid. ¹H NMR (400 MHz, DMSO) δ 8.36 (s, 1H),7.58-7.61 (dd, J=1.9, 6.9 Hz, 1H), 6.39 (d, J=8.7 Hz, 2H), 5.37 (br. s,1H), 4.91-5.06 (m, 3H), 4.54-4.57 (m, 2H); ESI-LC/MS (m/z): [M+H]⁺176.2, RT 1.65 min.

Intermediate I-263-bromo-N-(5-cyanopyridin-2-yl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

To a solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic acid (I-7,240 mg, 1 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.25 mL) and catalytic amounts of anhydrous dimethylformamide at rt.The reaction mixture was stirred for 30 minutes and subsequently thesolvent was removed under reduced pressure. To the residual acidchloride was added a solution of 6-(oxetan-3-ylamino)nicotinonitrile(I-25, 175 mg, 1 mmol) in dichloromethane (10 mL). The resultingreaction mixture was quickly transferred to a microwave vial and NaH(60% in mineral oil) (191 mg, 5 mmol) was added. The vial was heated ina microwave oven at 80° C. for 3 h. The reaction mixture was dilutedwith dichloromethane (15 mL) and subsequently washed with water, sat.NaHCO₃ solution and brine. The organic layer was dried over Na₂SO₄ andthe solvent was removed under reduced pressure. The resulting crudeproduct was purified by column chromatography over silica gel(chloroform/MeOH, 0-10% EtOAc) to afford 75 mg (20%) of3-bromo-N-(5-cyanopyridin-2-yl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide(I-26) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=7.0 Hz,1H), 8.16 (s, 1H), 8.02 (t, J=7.90 Hz, 1H), 7.53 (d, J=0.8 Hz, 1H),7.33-7.31 (m, 1H), 6.90-6.87 (m, 1H), 6.43 (d, J=10.1 Hz, 1H), 4.67-4.62(m, 1H), 4.52-4.43 (m, 2H), 4.25-4.19 (m, 1H), 4.03-3.98 (m, 1H);ESI-LC/MS (m/z): [M+H]⁺ 398.13, [(M+2)+H]⁺ 400.08, RT 1.25 min.

Intermediate I-27N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-bromo-N-(5-cyanopyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-27 was prepared according to the procedure described forthe synthesis of intermediate I-7 by replacing6-(oxetan-3-ylamino)nicotinonitrile with6-(1-(1H-pyrazol-1-yl)propan-2-ylamino)nicotinonitrile (283 mg, 1.25mmol). Microwave irradiation at 85° C. for 5 h. The resulting crudeproduct was purified by preparative TLC to afford 180 mg (32%) ofN-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-bromo-N-(5-cyanopyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide(I-27) as a pale brown highly viscious oil. ¹H NMR (400 MHz, DMSO-d₆) δ8.84 (d, J=2.2 Hz, 1H), 8.60 (d, J=7.1 Hz, 1H), 8.19 (s, 1H), 8.13 (d,J=2.2 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.38 (d, J=1.3 Hz, 1H), 7.27 (s,1H), 7.12 (d, J=8.3 Hz, 1H), 6.62 (d, J=1.7 Hz, 1H), 6.19 (t, J=1.7 Hz,1H), 5.06-5.10 (m, 1H), 4.82-4.87 (m, 1H), 4.43-4.47 (m, 1H), 1.36 (d,J=7.0 Hz, 3H); ESI-LC/MS (m/z): [M+H]⁺ 450.2, RT 3.73 min.

Intermediate I-28 (5-cyanopyridin-2-yl)(methyl)carbamic chloride

To a solution of bis (trichloromethyl) carbonate (50 mg, 0.17 mmol) intetrahydrofuran (2.0 mL) was added pyridine (0.04 mL, 0.510 mmol)dropwise under ice-cooling. After stirring under ice-cooling for 30 min,6-(methylamino)nicotinonitrile (68 mg, 0.510 mmol) was added and themixture was stirred at room temperature for 2.5 hours. The precipitatedsolid was filtered off. The filtrate containing(5-cyanopyridin-2-yl)(methyl)carbamic chloride (I-28) was directly usedfor next step.

Intermediate I-293-bromo-N-(5-cyanopyridin-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamide

To a solution of (5-cyanopyridin-2-yl)(methyl)carbamic chloride (I-28)in THF (2.0 mL) were added3-bromo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (137 mg, 0.680 mmol),triethylamine (0.14 mL, 1.021 mmol) and 4-dimethylaminopyridine (2.0 mg,0.017 mmol). The mixture was stirred at 60° C. for 1 h. Subsequently,water (25 mL) was added and the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over Na₂SO₄ andthe solvent was removed under reduced pressure. The resulting crudeproduct was purified by preparative TLC to afford 60 mg (44%) of3-bromo-N-(5-cyanopyridin-2-yl)-N-methyl-6,7-dihydropyrazolo-[1,5-a]pyrazine-5(4H)-carboxamide(I-29) as a off white solid. ¹H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.07(d, J=8.8 Hz, 1H), 7.60 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 4.53 (s, 2H),4.16 (t, J=4.9 Hz, 2H), 3.84 (t, J=4.9 Hz, 2H), 3.26 (s, 3H); ESI-LC/MS(m/z): [M+H]⁺ 360.91, [(M+2)+H]⁺ 362.93, RT 1.63 min.

Intermediate I-30 4-(chloromethyl)-N-methylbenzamide

To a solution 4-(chloromethyl)benzoyl chloride (1.0 g, 5.29 mmol) andmethylamine.HCl (1.0 g, 5.80 mmol) in dichloromethane (40 mL) was addedDIPEA (2.01 g, 15.6 mmol) at 0° C. and stirred for 1 h. The reactionmixture was extracted with water (1×50 mL). The organic layer wasextracted with brine (1×50 mL), dried over Na₂SO₄ and the solvent wasremoved under reduced pressure to afford 1.0 g (quantitative) of4-(chloromethyl)-N-methylbenzamide (I-30) as an off white solid. ¹H NMR(400 MHz, DMSO) δ 8.46 (d, J=3.5 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.51(d, J=8.3 Hz, 2H), 4.80 (s, 2H), 2.78 (d, J=4.4 Hz, 3H); ESI-LC/MS(m/z): [M+H]⁺ 184.2, RT 2.46 min.

Intermediate I-31 N-methyl-4-((trimethylstannyl)methyl)benzamide

A solution of 4-(chloromethyl)-N-methylbenzamide (I-30, 200 mg, 1.092mmol) and hexamethylditin (0.26 mL, 1.20 mmol) in toluene (5 mL) wasdegassed with argon gas for 15 min, followed by addition of Pd(PPh₃)₄(63.05 mg, 0.054 mmol). The mixture was heated to reflux for 8 h. Thereaction mixture was filtered and the solvent was removed under reducedpressure to afford 200 mg (58%) ofN-methyl-4-((trimethylstannyl)methyl)benzamide (I-31) as a brownsemi-solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (d, J=8.0 Hz, 2H), 7.00 (d,J=7.9 Hz, 2H), 2.99 (d, J=5.8 Hz, 2H), 2.35 (s, 2H), 0.04 (s, 9H); MS(m/z): [M+H]⁺ 314.0.

Intermediate I-32 4-(methylamino)cyclohexanecarbonitrile

To a solution of 4-cyanocyclohexanone (200 mg, 1.626 mmol) and CH₃NH₂(2M in THF) (0.8 mL, 1.626 mmol) in THF:CH₂Cl₂ (1:1) (4.0 mL) at 0° C.was added NaBH(OAc)₃ (689 mg, 3.252 mmol) and the resulting mixture wasstirred at rt for 48 h. Subsequently, the solvent was removed underreduced pressure and the residue was dissolved in ethyl acetate, washedwith water, brine, dried over Na₂SO₄ and concentrated to afford 200 mg(89%) of 4-(methylamino)cyclohexanecarbonitrile as a white solid. ¹H NMR(400 MHz, DMSO-d₆) 2.91 & 2.61 (two signals, 1H) 2.23-2.24 (m, 3H)1.02-1.99 (m, 9H); ELSD/MS (Method 3) (m/z): [M+H]⁺ 139.06.

Intermediate I-333-bromo-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(Example 84)

Intermediate I-33 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile with4-(methylamino)cyclohexane-carbonitrile. ¹H NMR (400 MHz, DMSO-d₆)8.77-8.79 (m, 1H) 8.23 (s, 1H) 7.58 (br.s, 1H) 6.95-6.97 (m, 1H) 4.30 &3.50 (two signals, 1H) 2.76-3.19 (m, 4H) 1.48-1.98 (m, 8H); ESI-LC/MS(Method 1) (m/z): [M+H]⁺ 361 & [M+2H]⁺ 363.

Intermediate I-34 2-amino-5-bromonicotinonitrile

To a solution of 2-aminonicotinonitrile (1.5 g, 12.5 mmol, 1.0 eq.) inAcOH (30 mL) was added Na₂CO₃ (1.3 g, 12.5 mmol). Bromine (0.7 ml, 13.8mmol) was added drop wise to the resulting suspension and reactionmixture was stirred at rt for 1 h. The orange precipitate formed wascollected by filtration, washed with water and dried to afford 2.0 g(80%) of I-34 as a yellow solid. ¹H NMR (400 MHz, DMSO) δ 8.27 (s, 1H),8.15 (s, 1H), 7.12 (brs, 2H).

Intermediate I-35 2-amino-5-bromonicotinonitrile

To a solution of 2-amino-5-bromopyridine (3 g, 17.3 mmol, 1.0 eq.)dissolved in DMF (10 ml) was added NCS (2.54 g, 19.07 mmol, 1.1 eq.) andthe resulting mixture was stirred at rt for 2 h. Subsequently, 5N NaOHwas used to adjust the pH of the reaction mixture to 7-8 followed byextraction with ethyl acetate (2×40 mL). The combined organic layerswere washed with water, brine, dried over anhydrous Na₂SO₄ solution andconcentrated under reduced pressure to afford 2.0 g (55%) of I-35 as ayellow solid. ¹H NMR (400 MHz, DMSO) δ 7.98 (s, 1H), 7.84 (s, 1H), 6.52(brs, 2H); ESI-LC/MS (m/z): [M+H]⁺ 206.96, [(M+2)+H]⁺ 208.91, RT 1.59min.

Intermediate I-36 2-amino-5-bromo-N,N-dimethylnicotinamide

To a stirred solution of 2-amino-5-bromo-3-carboxypyridine (1.0 g, 4.60mmol, 1.0 eq.), dimethylamine (0.227 g, 5.06 mmol, 1.1 eq.) and TEA (1.2ml, 9.20 mmol, 2.0 eq.) dissolved in THF (20 mL) was added diethylcyanophosphate (0.8 ml, 5.06 mmol, 1.1 eq.) drop wise. Stirring at rtwas continued for 4 h. The reaction mixture was partitioned betweenwater and ethyl acetate (2×30 mL). The combined organic layers werewashed with water, brine, dried over anhydrous Na₂SO₄ solution andconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography over silica gel (100-200 mesh) using a solventgradient of 4% MeOH in DCM as eluant to afford 500 mg (44%) of I-36 as aoff-white solid. ¹H NMR (400 MHz, DMSO) δ 8.05 (s, 1H), 7.54 (s, 1H),6.20 (brs, 2H), 2.90 (brs, 6H); ESI-LC/MS (m/z): [M+H]⁺ 244.01,[(M+2)+H]⁺ 246.01, RT 0.84 min.

Intermediate I-373-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

Intermediate I-37 was prepared according to the general boronic estersynthesis procedure A by utilizing 5-bromo-3-fluoropyridin-2-amine(reaction time: 16 h, temperature: 85° C.). ESI-LC/MS (m/z): [M+H]⁺239.1, RT 5.60 min.

Intermediate I-382,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Intermediate I-38 was prepared according to the general boronic estersynthesis procedure A by utilizing 4-bromo-2,6-dimethylaniline (reactiontime: 16 h, temperature: 85° C.). ESI-LC/MS (m/z): [M+H]⁺ 248.1, RT 6.67min.

Intermediate I-393-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

Intermediate I-39 was prepared according to the general boronic estersynthesis procedure B by utilizing 2-amino-3-methyl-5-bromopyridine(reaction time: 16 h, temperature: 90° C.). ESI-LC/MS (m/z): [M+H]⁺235.1, RT 1.26 min.

Intermediate I-405-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine

Intermediate I-40 was prepared according to the general boronic estersynthesis procedure A by utilizing 5-bromopyrimidin-2-amine (reactiontime: 5 h, temperature: 100° C.). ¹H NMR (400 MHz, DMSO) δ 8.59 (s, 2H),5.43 (brs, 2H), 1.32 (s, 12H);

Intermediate I-415-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine

Intermediate I-41 was prepared according to the general boronic estersynthesis procedure A by utilizing5-bromo-3-(trifluoromethyl)pyridin-2-amine (reaction time: 5 h,temperature: 100° C.). ¹H NMR (400 MHz, DMSO) δ 8.37 (s, 1H), 7.80 (s,1H), 6.89 (s, 2H), 1.27 (s, 12H); ESI-LC/MS (m/z): [M+H]⁺ 289.1, RT 4.83min.

Intermediate I-422-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile

Intermediate I-42 was prepared according to the general boronic estersynthesis procedure A by utilizing 2-amino-5-bromonicotinonitrile (I-34)(reaction time: 5 h, temperature: 100° C.). ¹H NMR (400 MHz, DMSO) δ8.57 (s, 1H), 8.08 (s, 1H), 5.42 (s, 2H), 1.27 (s, 12H); ESI-LC/MS(m/z): [M+H]⁺ 246.1, RT 5.05 min.

Intermediate I-433-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

Intermediate I-43 was prepared according to the general boronic estersynthesis procedure A by utilizing 5-bromo-3-chloropyridin-2-amine(I-35) (reaction time: 16 h, temperature: 100° C.). ¹H NMR (400 MHz,DMSO) δ 8.32 (s, 1H), 7.84 (s, 1H), 5.12 (s, 2H), 1.37 (s, 12H);ESI-LC/MS (m/z): [M+H]⁺ 256.5, RT 1.67 min.

Intermediate I-442-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide

Intermediate I-44 was prepared according to the general boronic estersynthesis procedure A by utilizing2-amino-5-bromo-N,N-dimethylnicotinamide (I-36) (reaction time: 16 h,temperature: 100° C.). ESI-LC/MS (m/z): [M-boronicacid]⁺ 210.1, RT 0.42min.

Intermediate I-453-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

Intermediate I-45 was prepared according to the general boronic estersynthesis procedure A by utilizing 2-amino-3-methoxy-5-bromopyridine(reaction time: 5 h, temperature: 100° C.). ¹H NMR (400 MHz, DMSO) δ8.03 (s, 1H), 7.19 (s, 1H), 5.17 (s, 2H), 3.84 (s, 3H), 1.27 (s, 12H).

Intermediate I-46 Methyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-5-carboxylate

A solution of pyrazolopyridine (100 mg, 0.568 mmol, 1.0 equiv.) andbis(pinacolato)diboron (158.75 mg, 0.625 mmol, 1.1 equiv.) in 1 mL THFwas treated with 2,2′-bipyridine (0.6 mg, 0.00224 mmol, 0.04 equiv.) and(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (0.75 mg, 0.00113 mmol,0.02 equiv.) at rt. The flask was charged with nitrogen gas, and theresulting mixture was allowed to stir at 50° C. for three hours. Thereaction was concentrated and the residue was purified by silica gelchromatography, eluting with CH₂Cl₂/EtOAc to give I-46. ¹H NMR (400 MHz,MeOD) δ 8.68 (dd, J=0.6, 7.2, 1H), 8.60-8.57 (m, 1H), 8.24 (s, 1H), 7.46(dd, J=1.9, 7.3, 1H), 3.98 (s, 3H), 1.39 (s, 12H).

Alternatively, a solution of pyrazolopyridine (750 mg, 4.26 mmol, 1.0equiv.) and bis(pinacolato)diboron (1.19 g, 4.69 mmol, 1.1 equiv.) in 10mL 1:1 THF/hexanes was treated with(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (84 mg, 0.128 mmol, 0.03equiv.) and 4,4′-di-tert-butyl-2,2′-bipyridine (68 mg, 0.256 mmol, 0.06equiv.) at rt. The flask was charged with nitrogen gas, and theresulting mixture was allowed to stir at rt overnight. The reaction wasconcentrated and the residue was purified by silica gel chromatography,eluting with hexanes/EtOAc to give intermediate I-46.

Intermediate I-473-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-5-carboxylicacid

A solution of ester (400 mg, 1.32 mmol, 1.0 equiv.) in 3 mL MeOH wastreated with 1 N aq. NaOH (3 mL, 3.0 mmol, 2.26 equiv.) at rt, and thenallowed to stir at rt for 30 minutes. The reaction mixture was thenneutralized with 3 mL 1 N aq. HCl, and the resulting white solid wasisolated by filtration. The filtrate was extracted with EtOAc and theorganic extracts were concentrated. The solid products were combined,and then diluted with 22 mL 10:1 CH₂Cl₂/THF before pinacol (157 mg, 1.32mmol, 1.0 equiv.) and 1 g MgSO4 were added. The resulting mixture wasallowed to stir at rt for 20 minutes, filtered, and concentrated underreduced pressure. The resulting white solid was triturated with hexanesto give the acid I-47, which was taken on without further purification.

Intermediate I-48 Methyl3-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxylate

A mixture of 2-chloro-5-(trifluoromethyl)pyridine (1.5 equiv.), arylboronic ester (1.0 equiv.), K2HPO4 (3.5 equiv.), and SiliaCat® DPP-Pd orPd(dppf)Cl2 (0.05-0.15 equiv.) in THF/water was allowed to heat at 150°C. in a microwave reactor for 40-60 minutes. After cooling to roomtemperature, the solvent was removed under reduced pressure. The cruderesidue was purified by mass-triggered HPLC or silica gel chromatographyto provide intermediate I-48.

Intermediate I-493-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxylicacid

Intermediate I-49 was prepared according to the procedure described forthe synthesis of intermediate I-7.

Intermediate I-50N-(4-cyanophenyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-50 was prepared according to the procedure described forthe synthesis of intermediate I-8.

Intermediate I-51 & I-52(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)methanol

A solution of acid (450 mg, 1.47 mmol, 1.0 equiv.) in 8 mL MeOH wastreated with SOCl₂ (300 μL, 4.14 mmol, 2.8 equiv.) dropwise and theresulting solution was allowed to heat at 50° C. overnight. The solutionwas diluted with 10 mL CH₂Cl₂, then washed with saturated aq. NaHCO₃,dried with Na₂SO₄, filtered, and concentrated under reduced pressure togive the desired ester (I-1), which was taken on without furtherpurification. ¹H NMR (400 MHz, CDCl₃,): 8.52 (m, 2H), 8.23 (s, 1H), 7.72(s, 4H), 7.40 (dd, J=1.59, 7.50 Hz, 1H), 3.96 (s, 3H).

A solution of the ester (100 mg, 0.31 mmol, 1.0 equiv.) in 3 mL CH₂Cl₂was allowed to cool to −78° C., and then a solution of DIBAL-H (1.0 M intoluene, 1.24 mL, 1.24 mmol, 4.0 equiv.) was added dropwise. Theresulting solution was allowed to stir at −78° C. for 90-120 minutes andthen was quenched with Na₂SO₄.10H₂O. The resulting mixture was allowedto stir at rt for 30 minutes, then was filtered and concentrated. Theresidue was purified by silica gel chromatography, eluting withhexanes/EtOAc to give the desired alcohol (I-51), as well as a smallamount of the corresponding aldehyde (I-52).

Intermediate I-535-(bromomethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine

A solution of alcohol (160 mg, 0.546 mmol, 1.0 equiv.) in 3 mL CH₂Cl₂was treated with PBr₃ (27 μL, 0.273 mmol, 0.5 equiv.) dropwise at rt,then was allowed to stir at rt for two hours. The solution was dilutedwith 20 mL CH₂Cl₂, then washed with saturated aq. NaHCO₃, dried withNa₂SO₄, filtered, and concentrated under reduced pressure to give thedesired bromide (I-53), which was taken on without further purification.

Intermediate I-543-bromo-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-54 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile with 4-fluoro-N-methylaniline.

Intermediate I-55N-(5-cyanopyridin-2-yl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-55 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile with 6-(methylamino)nicotinonitrile.

Intermediate I-56tert-butyl(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)carbamate

A mixture of pyrazolopyridine (153 mg, 0.50 mmol), DPPA (0.129 mL, 0.60mmol), t-BuOH (0.5 mL) and toluene (2.0 mL) was heated to 80° C.overnight. After cooling to room temperature, water was added to thereaction mixture and extracted with dichloromethane. The combinedorganic layers were washed with brine and dried over anhydrous Na₂SO₄.The solvent was removed and the product was purified by silica gelchromatography, eluting with ethyl acetate and hexanes. ¹H NMR (400 MHz,DMSO) δ 9.88 (s, 1H), 8.67 (d, J=7.6, 1 H), 8.40 (d, J=7.8, 1 H),8.30-8.07 (m, 1H), 7.91-7.64 (m, 4H), 7.00 (dd, J=2.1, 7.5, 1 H),1.59-1.41 (m, 9H).

Intermediate I-57 tert-butylmethyl(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)carbamate

NaH (7 mg, 0.15 mmol) was added to a solution of pyrazolopyridine in DMF(2.0 mL). The reaction stirred at room temperature for 15 minutes.Methyl iodide was added (0.018 mL, 0.12 mmol) and the reaction stirredfor 4 hours at room temperature. The reaction was quenched with waterand extracted with ethyl acetate. The combined organic layers werewashed with brine and dried over anhydrous Na₂SO₄. The solvent wasremoved and the material was purified by silica gel chromatography,eluting with ethyl acetate and hexanes. ¹H NMR (400 MHz, MeOD) δ 8.44(d, J=7.5, 1 H), 8.20 (s, 1H), 7.77-7.59 (m, 5H), 6.94 (d, J=5.3, 1H),3.26 (s, 3H), 1.41 (s, 9H).

Intermediate I-58N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-amine

To a solution of pyrazolopyridine (30 mg, 0.80 mmol) in dioxane (1.0 mL)was added 4N HCl in dioxane and the reaction stirred at room temperaturefor 2 hours. The resultant HCl salt was filtered and dried to give thedesired product. No further purification was necessary.

Intermediate I-59 tert-butyl4-fluorobenzyl(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)carbamate

Intermediate I-59 was prepared according to the procedure described forthe synthesis of intermediate I-57 by replacing methyl iodide with4-fluorobenzyl bromide.

Intermediate I-60tert-butyl((tetrahydro-2H-pyran-4-yl)methyl)(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)carbamate

Intermediate I-60 was prepared according to the procedure described forthe synthesis of intermediate I-25 by replacing methyl iodide with4-(bromomethyl)tetrahydro-2H-pyran.

Intermediate I-61N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-amine

Intermediate I-29 was prepared according to the procedure described forthe synthesis of intermediate I-57.

Intermediate I-62tert-butyl(3-bromopyrazolo[1,5-a]pyridin-5-yl)carbamate

To a mixture of pyrazolopyridine (240 mg, 1.00 mmol),diisopropylethylamine (0.160 mL, 1.00 mmol), t-BuOH (1.00 mL) andtoluene (4.00 mL) was added dry 4 angstrom molecular sieves. Thereaction stirred at room temperature for 30 minutes. DPPA (0.260 mL,1.20 mmol) was added and the reaction was heated to 80° C. overnight.After cooling to room temperature, the material was purified by silicagel chromatography, eluting with ethyl acetate and hexanes.

Intermediate I-63tert-butyl(3-bromopyrazolo[1,5-a]pyridin-5-yl)(methyl)carbamate

Intermediate I-63 was prepared according to the procedure described forthe synthesis of intermediate I-57.

Intermediate I-64 3-bromo-N-methylpyrazolo[1,5-a]pyridin-5-amine

Intermediate I-64 was prepared according to the procedure described forthe synthesis of intermediate I-58.

Intermediate I-65N-(3-bromopyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylbenzamide

To a solution of pyrazolopyridine (22.6 mg, 0.10 mmol) indichloromethane (2.0 mL) was added triethylamine (0.042 mL, 0.30 mmol)and a catalytic amount of DMAP. The reaction was cooled to 0° C. and4-fluorobenzoyl chloride was added. The reaction warmed to roomtemperature and stirred for 2 hours. The reaction was diluted with waterand extracted with dichloromethane. The organic extracts were washedwith brine and dried over anhydrous Na₂SO₄. The solvent was removed andthe material was purified by silica gel chromatography, eluting withethyl acetate and hexanes.

Intermediate I-663-bromo-N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-66 was prepared according to the procedure described forthe synthesis of intermediate I-8 by replacing4-(methylamino)benzonitrile withN-methyl-5-(methylsulfonyl)pyridin-2-amine.

Intermediate I-674-(1-(3-Bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one

Potassium tert-butoxide (75 mg, 0.666 mmol) was added to a stirredsolution of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (I-22, 100 mg,0.606 mmol) in dry THF at rt. After 5 min, a solution of3-bromo-5-(1-bromoethyl) pyrazolo[1,5-a]pyridine (I-18, 202 mg, 0.666mmol) in dry THF was added drop wise to reaction mixture at rt. Theresulting reaction mixture was heated to reflux for overnight andsubsequently cooled to room temperature. The reaction mixture wasdiluted with water (10 mL) and extracted with ethyl acetate (2×10 mL).The combined organic layers were dried over Na₂SO₄ and concentratedunder reduced pressure. The crude compound was purified by columnchromatography over silica gel (chloroform/EtOAc, 0-4% EtOAc) to afford110 mg (42%) of4-(1-(3-bromopyrazolo[1,5-a]pyridin-5-yl)ethyl)-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-oneI-67 as a yellow solid. ESI-LC/MS (Method 1) (m/z): [M+H]⁺ 389.9,[(M+2)+H]⁺ 391.9.

Intermediate I-68 6-(Ethylamino)nicotinonitrile

A solution of 2-bromo-5-cyanopyridine (75.0 g, 409.8 mmol), ethylaminesolution (2 M in THF) (300 mL) was stirred at 100° C. for 6 h in sealedtube. Then the solvent was distilled off and the residue was partitionedbetween dichloromethane (1000 mL) and water (2×500 mL). The separatedorganic layer was washed with brine, dried over anhyd. Na₂SO₄ andconcentrated in vacuo. The crude compound was passed through silica(100-200 mesh) column using a solvent gradient of 15% ethyl acetate inpet-ether as eluant to afford 52.0 g (86%) of6-(ethylamino)nicotinonitrile I-68 as a off white crystalline solid. ¹HNMR (DMSO-d₆) δ 8.37 (s, 1H), 7.64 (d, J=8.04 Hz, 1H), 7.54 (brs, 1H),6.51 (d, J=8.8 Hz, 1H), 3.30-3.25 (m, 2H), 1.13 (t, J=6.8 Hz, 3H).ESI/LC-MS: m/z 148.14 (M+H), r.t.=0.85 [Waters Acquity UPLC with 3100SQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 97:3H₂O (0.05% TFA):CH₃CN (0.05% TFA) to 2:98 H₂O (0.05% TFA):CH₃CN (0.05%TFA) for 4 minutes with 0.6 mL/min flow rate].

Intermediate I-693-Bromo-N-(5-cyanopyridin-2-yl)-N-ethylpyrazolo[1,5-a]pyridine-5-carboxamide

To a solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic acid I-7(25.0 g, 103.71 mmol) in dichloromethane (500 mL) was added oxalylchloride (25 mL, 290 mmol) followed by catalytic amountdimethylformamide (0.1 mL) at rt and stirred for 60 min. The resultantvolatiles were distilled-off under reduced pressure. The resulting crudeacid chloride was dissolved in dichloromethane (500 mL), and to theresulting solution were added a solution of6-(ethylamino)nicotinonitrile I-68 (15.3 g, 103.71 mmol) indichloromethane (100 mL) followed by DIPEA (50 mL, 286.4 mmol). Thereaction mixture was stirred for 2 h at rt and diluted withdichloromethane (500 mL). The organic layer was washed with water,brine, dried over anhydrous Na₂SO₄ and concentrated. The crude compoundwas purified by column chromatography over silica-gel (100-200 mesh)using a solvent gradient of 20-30% ethyl acetate and pet-ether as eluantto afford solid product. This solid was washed with 20% ethyl acetate inpet-ether and dried to obtain 24.0 g (63%) of3-bromo-N-(5-cyanopyridin-2-yl)-N-ethylpyrazolo[1,5-a]pyridine-5-carboxamideI-69 as a white solid. ¹H NMR (400 MHz, DMSO) δ 8.81 (d, J=2.0 Hz, 1H),8.65 (d, J=7.2 Hz, 1H), 8.20-8.22 (m, 2H), 7.54 (s, 1H), 7.49 (d, J=8.4Hz, 1H), 6.75 (dd, J=1.6, 6.8 Hz, 1H), 4.09 (q, J=7.2, 6.0 Hz, 2H), 1.20(t, J=6.8 Hz, 3H); ESI-LC/MS: m/z 372.12 [(M+2)+H]; r.t.=1.85 [WatersAcquity UPLC with 3100 SQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.1% formic acid):CH₃CN (0.1% formicacid) to 10:90 H₂O (0.1% formic acid):CH₃CN (0.1% formic acid) for 5minutes with 0.4 mL/min flow rate].

Intermediate I-70 6-(isopropylamino)nicotinonitrile

A solution of 2-bromo-5-cyanopyridine (20 g, 109.29 mmol) andisopropylamine (12.9 mL, 150.15 mmol) was maintained at 80° C. for 16 hin a sealed tube. The reaction mixture was diluted with water andextracted with ethyl acetate (2×500 mL). The combined organic layer waswashed with water, brine solution, dried over anhydrous Na₂SO₄ andconcentrated. The crude product was purified by column chromatographyover silica-gel (100-200 mesh) using a solvent gradient of 20% ethylacetate and pet-ether to afford 14 g (79%) of6-(isopropylamino)nicotinonitrile 1 as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.34 (d, J=1.8 Hz, 1H), 7.55 (dd, J=2.1, 8.7 Hz, 1H), 6.33 (d,J=8.7 Hz, 1H), 4.87 (br. s, 1H), 3.96-3.99 (m, 1H), 1.26 (d, J=6.6 Hz,6H).

Intermediate I-713-Bromo-N-(5-cyanopyridin-2-yl)-N-isopropylpyrazolo[1,5-a]pyridine-5-carboxamide

To a solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic acid I-7 (6g, 25.0 mmol) in dichloromethane (20 mL) were added oxalyl chloride (6.0mL, 69.5 mmol) followed by catalytic amount dimethylformamide (0.01 mL)at rt and stirred for 30 min. The resultant volatiles were distilled-offunder reduced pressure to afford residue of acid chloride. The acidchloride was dissolved in dichloromethane (20 mL), and to the solutionwas added DIPEA (12 mL, 68.73 mmol) and6-(isopropylamino)nicotinonitrile I-70 (4 g, 24.8 mmol). The resultingreaction mixture was stirred for 16 h at rt and diluted withdichloromethane (100 mL). The organic layer was washed with water,brine, dried over anhydrous Na₂SO₄ and concentrated. The crude compoundwas purified by column chromatography over silica (100-200 mesh) using asolvent gradient of 30% ethyl acetate in pet-ether as eluant to afford 4g (42%) of3-bromo-N-(5-cyanopyridin-2-yl)-N-isopropylpyrazolo[1,5-a]pyridine-5-carboxamideI-71 as a yellow solid ¹H NMR (400 MHz, DMSO) δ 8.92 (m, 1H), 8.61 (d,J=7.6 Hz, 1H), 8.19-8.23 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.36 (s, 1H),6.71 (dd, J=1.6, 6.8 Hz, 1H), 4.88-4.90 (m, 1H), 1.31 (d, J=6.4 Hz, 6H);ESI-LC/MS: m/z 386.09 [(M+2)+H]; r.t.=1.71. [Waters Acquity UPLC withQuattroMicro; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradientof 80:20 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) for 3 minutes with 0.4 mL/min flow rate].

Intermediate I-72 tert-Butyl2-(4-cyanophenyl)-1-methylhydrazinecarboxylate

To a solution of 4-cyanophenylboronic acid (2.0 g, 13.62 mmol),tert-butyl 1-methyl hydrazinecarboxylate (2.0 g, 13.48 mmol) in1,2-dichloroethane (10 mL), copper acetate (2.71 g, 13.6 mmol) and TEA(1.85 mL, 13.3 mmol) were added and stirred at 50° C. for 2 h. Thereaction mixture was partitioned between water (50 mL) and ethyl acetate(2×50 mL). The ethyl acetate layer was washed with brine (100 mL), driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude compoundwas purified by column chromatography over silica (100-200 mesh) using asolvent gradient of 20% ethyl acetate in chloroform as eluant to afford1.2 g (36%) of tert-butyl 2-(4-cyanophenyl)-1-methylhydrazinecarboxylateI-72 as an off white solid. ¹H NMR (400 MHz, DMSO-d₆). ESI/LC-MS: m/z:248.08, (M+H), 97.78% ¹H NMR (400 MHz, CDCl₃) δ 8.78 (s, 1H), 7.58 (d,J=8.8 Hz, 2H), 6.65 (d, J=8.8 Hz, 2H), 3.06 (s, 3H), 1.36 (s, 9H);ESI-LC/MS m/z 248.08 (M+H); r.t.=2.76 [Waters Acquity UPLC withQuattroMicro; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradientof 98:2 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 0:100 H₂O (0.025%TFA):CH₃CN (0.025% TFA) for 5 minutes with 0.4 mL/min flow rate].

Intermediate I-73 tert-Butyl2-(3-bromopyrazolo[1,5-a]pyridine-5-carbonyl)-2-(4-cyanophenyl)-1-methylhydrazinecarboxylate

To a solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic acid I-7(1.0 g, 4.16 mmol) in dichloromethane (30 mL) were added oxalyl chloride(1.5 mL, 17.37 mmol) followed by catalytic amount ofN,N-dimethylformamide (0.01 mL) at rt and stirred for 30 min. Theresultant volatiles were distilled-off under reduced pressure. The crudeacid chloride was dissolved in dichloromethane (20 mL), and to theresulting solution were added DIPEA (3.0 mL, 17.18 mmol), tert-butyl2-(4-cyanophenyl)-1-methylhydrazinecarboxylate I-72 (800 mg, 3.24 mmol).The reaction mixture was stirred for 48 h at 50° C. and diluted withdichloromethane (150 mL). The organic layer was washed with water,brine, dried over anhydrous Na₂SO₄ and the solvent was distilled offunder reduced pressure. The crude compound was purified by columnchromatography over silica gel (100-200 mesh) using a solvent gradientof 40% ethyl acetate in pet-ether as eluant to afford 700 mg (36%) oftert-butyl2-(3-bromopyrazolo[1,5-a]pyridine-5-carbonyl)-2-(4-cyanophenyl)-1-methylhydrazine carboxylate I-73 as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.81 (d, J=7.2 Hz, 1H), 8.28 (s, 1H), 7.89-7.91 (m, 2H), 7.71 (s, 1H),7.45-7.51 (m, 2H), 6.99-7.03 (m, 1H), 3.12 (s, 3H), 1.34 (s, 9H).

Intermediate I-74 6-(cyclopropylamino)nicotinonitrile

Intermediate I-74 may be prepared by reacting 2-bromo-5-cyanopyridinewith cyclopropylamine following the procedure for the synthesis ofIntermediate I-70.

Intermediate I-753-Bromo-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-75 may be prepared by reacting Intermediate I-7 withIntermediate I-74 according the procedure described for the synthesis ofIntermediate I-71.

Intermediate I-76 N-ethyl-5-fluoropyridin-2-amine

Intermediate I-76 may be prepared by reacting 2-bromo-5-fluoropyridinewith ethylamine according to the procedure described for the synthesisof Intermediate I-68.

Intermediate I-773-bromo-N-ethyl-N-(5-fluoropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-77 may be prepared by reacting Intermediate I-7 withIntermediate I-76 according to the procedure described for the synthesisof Intermediate I-69.

Intermediate I-78 N-ethyl-5-(trifluoromethyl)pyridin-2-amine

Intermediate I-78 may be prepared by reacting2-bromo-5-(trifluoromethyl)pyridine with ethylamine according to theprocedure described for the synthesis of Intermediate I-68.

Intermediate I-793-bromo-N-ethyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Intermediate I-79 may be prepared by reacting Intermediate I-7 withIntermediate I-78 according to the procedure described for the synthesisof Intermediate I-69.

Intermediate I-80N-(3-bromopyrazolo[1,5-a]pyridin-5-yl)-5-cyano-N-methylpicolinamide

Intermediate I-80 may be prepared by reacting Intermediate I-64 with5-cyanopicolinoyl chloride according to the procedure described for thesynthesis of Intermediate I-65.

Example 1N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

A solution of acid (1.0 equiv.) in CH₂Cl₂ (˜0.05-0.1 M) was treated withoxalyl chloride (2.0-3.0 equiv.) and a catalytic amount of DMF. Theresulting solution was allowed to stir at rt for between five minutesand one hour, then was concentrated and dried briefly under high vacuum.The resulting acid chloride was diluted with CH₂Cl₂ (˜0.05-0.1 M), andto this solution was added 4-(methylamino)benzonitrile (1.1-3.0 equiv.)and either DIEA or Et3N (3.0 equiv.). The resulting mixture was allowedto stir at rt until complete conversion (generally less than threehours). The solvent was removed under reduced pressure, and the residuewas purified by silica gel chromatography, eluting with hexanes/ethylacetate to provide 1. ¹H NMR (400 MHz, CDCl3) δ 8.30 (dd, J=0.7, 7.3,1H), 8.16 (s, 1H), 7.82 (m, 1H), 7.66 (d, J=8.2, 2H), 7.60 (d, J=8.6,2H), 7.47 (d, J=8.1, 2H), 7.23 (obscured by CDCl₃ peak, 2H), 6.64 (dd,J=1.8, 7.3, 1H), 3.54 (s, 3H). ESI-LC/MS m/z 421.1 (M+H)+; r.t.=1.871.

Example 24-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)methyl)aniline

A solution of N-methyl aniline (18.8 mg, 0.15 mmol, 1.5 equiv.) in 0.5mL THF was allowed to cool to 0° C., then a solution of NaHMDS (1.0 M inTHF, 150 μL, 0.15 mmol, 1.5 equiv.) was added dropwise. After allowingthe resulting solution to stir at 0° C. for 10 minutes, a solution ofbromide (35.4 mg, 0.10 mmol, 1.0 equiv.) in 0.5 mL THF was addeddropwise. The reaction mixture was allowed to stir at 0° C. for another10-20 minutes, and then the reaction was quenched with water andconcentrated under reduced pressure. The residue was diluted withMeOH-DMSO and the resulting solution was purified by mass-triggered HPLCto provide 2 as the TFA salt. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=7.2,1H), 8.14 (s, 1H), 7.65 (d, J=8.3, 2H), 7.59 (m, 3H), 6.94 (m, 2H), 6.72(m, 3H), 4.48 (s, 2H), 2.99 (s, 3H). ESI-MS (m/z): [M+H]⁺ 400.2, RT2.409 min.

Example 3N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 3 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile with4-chloro-N-methylaniline. ESI-LC/MS m/z 430.1 (M+H)+; r.t.=2.275.

Example 4N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 4 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile with4-fluoro-N-methylaniline. ESI-LC/MS m/z 414.1 (M+H)+; r.t.=2.165.

Example 5N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 5 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile withN,5-dimethylpyridin-2-amine. ESI-LC/MS m/z 411.2 (M+H)+; r.t.=2.005.

Example 64-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)methyl)aniline

Example 6 was prepared according to the procedure described for thesynthesis of Example 2 by replacing 4-fluoro-N-methylaniline with4-chloro-N-methylaniline. ¹H NMR (400 MHz, CDCl3) δ 8.48 (d, J=7.2, 1H), 8.15 (s, 1H), 7.66 (d, J=8.3, 2H), 7.62-7.55 (m, 3H), 7.18 (d,J=9.1, 2H), 6.74-6.65 (m, 3H), 4.53 (s, 2H), 3.03 (s, 3H). ESI-MS (m/z):[M+H]⁺ 416.1, RT 2.5357 min.

Example 7N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]114yridine-5-yl)methyl)pyridine-2-amine

Example 7 was prepared according to the procedure described for thesynthesis of Example 2 by replacing 4-fluoro-N-methylaniline withN,5-dimethylpyridin-2-amine (2.0 equiv) and using 2.0 equiv of NaHMDS.¹H NMR (400 MHz, CDCl3) δ 8.50 (d, J=7.2, 1 H), 8.18 (s, 1H), 8.03 (s,1H), 7.73-7.65 (m, 3H), 7.62 (d, J=8.2, 3H), 6.82 (d, J=9.2, 1H), 6.66(dd, J=1.8, 7.2, 1H), 4.88 (s, 2H), 3.37 (s, 3H), 2.27 (s, 3H). ESI-MS(m/z): [M+H]⁺ 397.2, RT 1.5837 min.

Example 85-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine

A mixture of pyrazolopyridine alkyl bromide (I-53) (17.7 mg, 0.05 mmol,1.0 equiv.), 4-fluorophenol (11.2 mg, 0.1 mmol, 2.0 equiv.), and Cs₂CO₃(48 mg, 0.15 mmol, 3.0 equiv.) in acetone was allowed to stir at rt forone hour. The mixture was filtered and purified by mass-triggered HPLCto provide 8. ¹H NMR (400 MHz, CDCl3) δ 8.51 (d, J=7.2, 1 H), 8.17 (s,1H), 7.83 (s, 1H), 7.68 (d, J=1.6, 4H), 7.05-6.82 (m, 5H), 5.07 (s, 2H).ESI-MS (m/z): [M+H]⁺ 387.1, RT 2.5104 min.

Example 9N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 9 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile with4-((2-methoxyethyl)amino)benzonitrile. ESI-LC/MS m/z 465.2 (M+H)+;r.t.=2.098.

Example 10N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 10 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile with4-((2-(dimethylamino)ethyl)amino)benzonitrile. ESI-LC/MS m/z 478.2(M+H)+; r.t.=1.550.

Example 11N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 11 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile with4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzonitrile. ESI-LC/MS m/z505.2 (M+H)+; r.t.=1.997.

Example 12N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 12 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile with4-(methylsulfonyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline.ESI-LC/MS m/z 558.2 (M+H)+; r.t.=1.828.

Example 13N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 13 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile with6-(methylamino)nicotinonitrile. Purification by silica gelchromatography, eluting with hexane/ethyl acetate provided the desiredproduct (13). ¹H NMR (400 MHz, CDCl3) δ 8.67 (dd, J=0.8, 2.3, 1H), 8.41(dd, J=0.7, 7.2, 1H), 8.21 (s, 1H), 7.98 (m, 1H), 7.80 (dd, J=2.3, 8.6,1H), 7.69 (d, J=8.2, 2H), 7.59 (d, J=8.1, 2H), 7.35 (dd, J=0.8, 8.7,1H), 6.73 (dd, J=1.9, 7.2, 1H), 3.62 (s, 3H). ESI-MS (m/z): [M+H]⁺422.1, RT 1.9712 min. Anal. Calcd for C₂₂H₁₄F₃N₅O+0.2H₂O: C, 62.18; H,3.42; N, 16.48. Found: C, 62.26, 62.26; H, 3.39, 3.38; N, 16.40, 16.38.

Example 14N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 14 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile withN,5-dimethylpyridin-3-amine. The reaction was purified by mass-triggeredHPLC to provide the desired product, 14. ESI-MS (m/z): [M+H]⁺ 411.2, RT1.5164 min.

Example 155-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine

Example 15 was prepared according to the procedure described for thesynthesis of Example 8 by replacing 4-fluorophenol with 1.5 equiv. of5-methylpyridin-2-ol and using 2.0 equiv. Cs₂CO₃ in acetonitrile (toreplace acetone). The reaction was purified by mass-triggered HPLC toprovide the desired product. ¹H NMR (400 MHz, MeOD) δ 8.57 (d, J=7.2,1H), 8.32 (s, 1H), 7.91 (s, 1H), 7.84 (d, J=8.2, 2H), 7.74 (d, J=8.3,2H), 7.61 (s, 1H), 7.47 (dd, J=2.5, 9.2, 1H), 6.94 (dd, J=1.8, 7.2, 1H),6.57 (d, J=9.2, 1H), 5.26 (s, 2H), 2.12 (s, 3H). ESI-MS (m/z): [M+H]⁺384.1, RT 1.8029 min.

Example 165-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine

A mixture of pyrazolopyridine aldehyde (I-52) (48 mg, 0.165 mmol, 1.0equiv.) and Wittig salt (74 mg, 0.18 mmol, 1.1 equiv.) in acetonitrilewas treated with DBU (28 mg, 0.18 mmol, 1.1 equiv.). The resultingmixture was allowed to stir at 50° C. for two hours, and then thereaction mixture was concentrated. The residue was purified by silicagel chromatography, eluting with hexanes/EtOAc to give the desiredolefin. A solution of olefin (22 mg, 0.0575 mmol, 1.0 equiv.) in 5 mLEtOH was purged with nitrogen gas, then 10% Pd/C (5 mg) was added. Theresulting mixture was purged with hydrogen gas and allowed to stir atroom temperature overnight under an atmosphere of hydrogen gas. Themixture was then filtered through Celite® and purified by mass-triggeredHPLC to provide the desired product. ¹H NMR (400 MHz, CDCl3) δ 8.40 (d,J=7.6, 1H), 8.12 (s, 1H), 7.66 (d, J=8.3, 2H), 7.59 (d, J=8.2, 2H), 7.42(s, 1H), 7.10 (dd, J=5.4, 8.6, 2H), 6.96 (t, J=8.7, 2H), 6.63 (dd,J=1.8, 7.1, 1H), 2.95 (s, 4H). ESI-MS (m/z): [M+H]⁺ 385.2, RT 2.5863min.

Example 17N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of aryl bromide (I-8) (1.0 equiv.),(1-methyl-1H-indazol-5-yl)boronic acid (1.5 equiv.), KH₂PO₄ (3.5equiv.), and SiliaCat® DPP-Pd or Pd(dppf)Cl₂ (0.05-0.15 equiv.) inTHF/water was allowed to heat at 150° C. in a microwave reactor for40-60 minutes. The solvent was removed under reduced pressure and thecrude material was purified by silica gel chromatography eluting withethyl acetate and hexanes. ¹H NMR (400 MHz, CDCl3) δ 8.28 (dd, J=0.8,7.4, 1H), 8.12 (s, 1H), 8.01 (d, J=0.8, 1H), 7.80 (m, 1H), 7.65 (s, 1H),7.60 (d, J=8.6, 2H), 7.44 (d, J=8.6, 1H), 7.36 (dd, J=1.5, 8.6, 1H),7.22 (obscured by CDCl₃ peak, 2H), 6.62 (dd, J=1.9, 7.3, 1 H), 4.11 (s,3H), 3.53 (s, 3H). ESI-MS (m/z): [M+H]⁺ 407.1, RT 1.6596 min. Anal.Calcd for C₂₄H₁₈N₆O+0.1H₂O: C, 70.61; H, 4.49; N, 20.59. Found: C,70.59, 70.57; H, 4.43, 4.43; N, 20.57, 20.57.

Example 183-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of aryl bromide (I-8) (1.0 equiv.),(6-acetamidopyridin-3-yl)boronic acid (1.5 equiv.), K₂CO₃ (3.0 equiv.),and Pd(dppf)Cl₂ (0.05-0.15 equiv.) in DME/water was allowed to heat at110° C. for two hours. Following extraction of the reaction mixture withCH₂Cl₂, the combined organic extracts were concentrated and the residuewas purified by silica gel chromatography, eluting with hexanes/EtOAc togive the desired product. ¹H NMR (400 MHz, MeOD) δ 8.48 (dd, J=0.8, 7.0,1 H), 8.35 (d, J=2.4, 1 H), 8.26 (s, 1H), 8.18 (d, J=8.4, 1 H), 7.81(dd, J=2.4, 8.6, 1 H), 7.78 (s, 1H), 7.71 (d, J=8.6, 2H), 7.48 (d,J=8.6, 2H), 6.87 (dd, J=1.8, 7.3, 1 H), 3.55 (s, 3H), 2.21 (s, 3H).ESI-MS (m/z): [M+H]⁺ 411.2, RT 1.2806 min.

Example 193-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 19 was prepared according to the procedure described for thesynthesis of Example 17 by replacing (1-methyl-1H-indazol-5-yl)boronicacid with (4-carbamoylphenyl)boronic acid. The reaction was purified bysilica gel chromatography, eluting with hexanes/EtOAc to give 19 as thedesired product. ¹H NMR (400 MHz, MeOD) δ 8.49 (dd, J=0.8, 7.2, 1 H),8.31 (s, 1H), 7.97 (d, J=8.4, 2H), 7.84 (s, 1H), 7.74 (d, J=8.6, 2H),7.53-7.46 (2d, J=8.6, 4H), 6.91 (dd, J=1.6, 7.2, 1 H), 3.56 (s, 3H).ESI-MS (m/z): [M+H]⁺ 397.2, RT 1.3648 min. Anal. Calcd forC₂₃H₁₇N₅O₂+0.5H₂O: C, 68.31; H, 4.49; N, 17.32. Found: C, 68.61, 68.54;H, 4.46, 4.40; N, 17.07, 16.99.

Example 203-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of aryl bromide (I-54) (1.0 equiv.),(4-carbamoylphenyl)boronic acid (1.5 equiv.), KH₂PO₄ (3.5 equiv.), andSiliaCat® DPP-Pd or Pd(dppf)Cl2 (0.05-0.15 equiv.) in THF/water wasallowed to heat at 150° C. in a microwave reactor for 40-60 minutes. Thesolvent was removed under reduced pressure and the crude material waspurified by silica gel chromatography, eluting with hexanes/EtOAc togive 20 as the desired product. ¹H NMR (400 MHz, CDCl3) δ 8.28 (dd,J=0.8, 7.2, 1H), 8.14 (s, 1H), 7.84 (dt, J=2.0, 8.4, 2H), 7.74 (s, 1H),7.42 (d, J=8.4, 2H), 7.14-7.08 (m, 2H), 7.06-6.99 (m, 2H), 6.75 (dd,J=1.8, 7.4, 1H), 6.07 (br s, 1H), 5.56 (br s, 1H), 3.49 (s, 3H). ESI-MS(m/z): [M+H]⁺ 389.1, RT 1.4322 min. Anal. Calcd for C₂₂H₁₇FN₄O₂+0.4H₂O:C, 66.79; H, 4.54; N, 14.16. Found: C, 66.97, 66.74; H, 4.49, 4.43; N,14.20, 14.16.

Example 215-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine

A solution of pyrazolopyridine alkyl bromide (I-53) (45 mg, 0.127 mmol,1.0 equiv.) and 4-fluorobenzenethiol (24 mg, 0.19 mmol, 1.5 equiv.) inCH₂Cl₂ was treated with DIEA (33 mg, 0.254 mmol, 2.0 equiv.) and theresulting solution was allowed to stir at rt for 20 minutes. Thereaction was concentrated and the residue was purified by silica gelchromatography, eluting with hexanes/EtOAc to give 21 as the desiredproduct. ¹H NMR (400 MHz, CDCl3) δ 8.41 (d, J=7.2, 1H), 8.11 (s, 1H),7.64 (d, J=8.1, 2H), 7.50 (d, J=8.1, 2H), 7.36-7.27 (m, 3H), 6.96 (t,J=8.7, 2H), 6.78 (dd, J=1.9, 7.2, 1 H), 4.00 (s, 2H). ESI-MS (m/z):[M+H]⁺ 403.1, RT 2.5275 min.

Example 225-(((4-fluorophenyl)sulfinyl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine

A solution of sulfide (21) (30 mg, 0.75 mmol, 1.0 equiv.) in 1 mL ofCH₂Cl₂ was treated with m-CPBA (77% purity, 16.6 mg, 0.75 mmol, 1.0equiv.) and the resulting mixture was allowed to stir at rt for 20minutes. The reaction was concentrated and the residue was purified bysilica gel chromatography, eluting with hexanes/EtOAc to give 22 as thedesired product. ¹H NMR (400 MHz, CDCl3) δ 8.38 (d, J=7.2, 1H), 8.15 (s,1H), 7.66 (d, J=8.2, 2H), 7.53 (d, J=8.0, 2H), 7.49-7.43 (m, 2H), 7.32(d, J=0.7, 1 H), 7.20-7.13 (m, 2H), 6.46 (dd, J=1.8, 7.1, 1H), 4.12 (d,J=12.9, 1H), 3.95 (d, J=12.9, 1H). ESI-MS (m/z): [M+H]⁺ 419.1, RT 2.0051min.

Example 233-(4-(1H-pyrazol-5-yl)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 23 was prepared according to the procedure described for thesynthesis of Example 17 by replacing (1-methyl-1H-indazol-5-yl)boronicacid with ((4-(1H-pyrazol-5-yl)phenyl)boronic acid. The reaction waspurified by mass-triggered HPLC to provide 23 as the desired product. ¹HNMR (400 MHz, CDCl3) δ 8.30 (dd, J=0.9, 7.3, 1 H), 8.15 (s, 1H),7.83-7.78 (m, 3H), 7.65 (d, J=2.3, 1 H), 7.64-7.59 (m, 2H), 7.41-7.34(m, 2H), 7.25-7.21 (m, 2H), 6.70-6.65 (m, 2H), 3.54 (s, 3H). ESI-MS(m/z): [M+H]⁺ 419.2, RT 1.5585 min.

Example 24N-(4-cyanophenyl)-N-methyl-3-(5-(trifluoromethyl)122yridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of 2-chloro-5-(trifluoromethyl)pyridine (1.0 equiv.), I-50(1.5 equiv.), KH₂PO₄ (3.5 equiv.), and SiliaCat® DPP-Pd or Pd(dppf)Cl2(0.05-0.15 equiv.) in THF/water was allowed to heat at 150° C. in amicrowave reactor for 40-60 minutes. The solvent was removed underreduced pressure and the crude material was purified by silica gelchromatography eluting with ethyl acetate and hexanes. ¹H NMR (400 MHz,CDCl3) δ 8.77 (s, 1H), 8.63 (dd, J=0.8, 2.0, 1H), 8.40 (s, 1H), 8.33(dd, J=0.8, 7.2, 1H), 7.88 (dd, J=2.4, 8.4, 1H), 7.66 (d, J=8.4, 1H),7.56 (dt, J=2.1, 8.7, 2H), 7.25 (app dt, obscured by CDCl3 peak, 2H),6.79 (dd, J=1.9, 7.2, 1 H), 3.56 (s, 3H). ESI-MS (m/z): [M+H]⁺ 422.1, RT1.8535 min.

Example 25N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-(trifluoromethyl)122yridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of 2-chloro-5-(trifluoromethyl)pyridine (1.0 equiv.), I-50(1.5 equiv.), KH₂PO₄ (3.5 equiv.), and SiliaCat® DPP-Pd or Pd(dppf)Cl2(0.05-0.15 equiv.) in THF/water was allowed to heat at 150° C. in amicrowave reactor for 40-60 minutes. The solvent was removed underreduced pressure and the crude material was purified by silica gelchromatography eluting with ethyl acetate and hexanes. ¹H NMR (400 MHz,MeOD) δ 8.88-8.84 (m, 1H), 8.73 (dd, J=0.8, 2.4, 1 H), 8.69 (s, 1H),8.65 (dd, J=1.2, 2.4, 1 H), 8.61 (dd, J=0.8, 7.2, 1 H), 8.09-8.02 (m,2H), 7.99 (d, J=8.5, 1 H), 7.53 (dd, J=0.8, 8.5, 1 H), 7.02 (dd, J=2.0,7.2, 1 H), 3.65 (s, 3H). ESI-MS (m/z): [M+H]⁺ 423.0, RT 1.8535 min.

Example 26(S)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

A solution of the aniline (30 mg, 0.082 mmol, 1.0 equiv.) in CH₂Cl₂ wastreated with N-Boc-L-Ala-OH (18.5 mg, 0.098 mmol, 1.2 equiv.), followedby HATU (34.3 mg, 0.0902 mmol, 1.1 equiv.) and DIEA (21 mg, 0.16 mmol,2.0 equiv.). The resulting mixture was allowed to stir at rt for twohours, and then was purified by silica gel chromatography, eluting withCH₂Cl₂/EtOAc to give the desired N-Boc coupled product. The N-Bocalanine amide (35 mg) was dissolved in 1 mL CH₂Cl₂ and 1 mL TFA wasadded. The resulting solution was allowed to stir at rt for 30 minutes,and the solvents were removed under reduced pressure. The residue wastaken up in 2 mL EtOAc and 3 mL hexanes was added to precipitate theproduct TFA salt, which was isolated by filtration and dried under highvacuum. A solution of the TFA salt (16 mg) in 20% MeOH/CH₂Cl₂ was runthrough a 100 mg cartridge of Varian Stratospheres™ PL-HCO3 MP resin.The solvents were removed under reduced pressure, and the residue wasdissolved in 10% MeOH/CH₂Cl₂ and run through a 200 mg cartridge ofVarian Stratospheres™ PL-HCO3 MP resin. The solvents were removed underreduced pressure to provide 26 as the free base. ¹H NMR (400 MHz, MeOD)δ 8.45 (dd, J=0.8, 7.2, 1 H), 8.18 (s, 1H), 7.75-7.71 (m, 3H), 7.68 (d,J=8.6, 2H), 7.47 (d, J=8.6, 2H), 7.32 (d, J=8.6, 2H), 6.87 (dd, J=1.8,7.3, 1H), 3.61 (q, J=6.9, 1H), 3.55 (s, 3H), 1.40 (d, J=6.9, 3H). ESI-MS(m/z): [M+H]⁺ 439.1, RT 1.1711 min.

Example 273-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 27 was prepared according to the procedure described for thesynthesis of Example 25 by replacing2-chloro-5-(trifluoromethyl)pyridine with 6-chloronicotinamide.Purification by silica gel chromatography, eluting with hexanes/EtOAc,then 5% MeOH/CH₂Cl₂ gave the desired product. ¹H NMR (400 MHz, DMSO) δ9.04 (dd, J=0.8, 2.3, 1H), 8.81 (s, 1H), 8.68 (dd, J=0.8, 7.2, 1H), 8.56(s, 1H), 8.22 (dd, J=2.3, 8.4, 1H), 8.14 (s, 1H), 7.94 (d, J=8.3, 1H),7.81 (d, J=8.7, 2H), 7.58 (s, 1H), 7.54 (d, J=8.6, 2H), 6.85 (dd, J=1.9,7.2, 1 H), 3.47 (s, 3H). ESI-MS (m/z): [M+H]⁺ 397.1, RT 1.2047 min.

Example 284-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzamide

To a solution of pyrazolopyridine (15 mg, 0.05 mmol) in CH₂Cl₂containing triethylamine (0.020 mL, 3.00 mmol) at 0° C. was added4-cyanobenzoyl chloride (14 mg, 1.50 mmol). The reaction was allowed towarm to room temperature and stir for 1 hour. The reaction was dilutedwith water and extracted with dichloromethane. The organic extracts werewashed with brine and dried over anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by mass-trigger HPLC. ¹H NMR (400MHz, MeOD) δ 8.54 (d, J=7.4, 1H), 8.29 (s, 1H), 7.66 (ddd, J=8.1, 12.9,29.8, 9H), 6.92 (dd, J=2.2, 7.4, 1H), 3.56 (s, 3H); MS m/z 421.0 (M+H)⁺.

Example 294-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzamide

Example 29 was prepared according to the procedure described for thesynthesis of Example 28 by replacing 4-cyanobenzoyl chloride with4-fluorobenzoyl chloride. ¹H NMR (400 MHz, MeOD) δ 8.43 (d, J=7.4, 1H),8.18 (s, 1H), 8.06-7.84 (m, 1H), 7.60 (d, J=8.3, 2H), 7.50 (d, J=8.5,3H), 7.40 (dd, J=5.3, 8.8, 2H), 7.08 (t, J=8.8, 1H), 6.96 (t, J=8.8,2H), 6.78 (d, J=7.4, 1H), 3.45 (s, 3H); MS m/z 414.1 (M+H)⁺.

Example 304-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide

To a solution of pyrazolopyridine (15 mg, 0.05 mmol) and a catalyticamount of DMAP in pyridine (1.0 mL) at 0° C. was added4-cyanobenzene-1-sulfonyl chloride (18 mg, 0.08 mmol). The reaction wasallowed to warm to room temperature and stir overnight. The reaction wasdiluted with water and extracted with dichloromethane. The organicextracts were washed with saturated CuSO₄ solution and brine, dried overanhydrous Na₂SO₄. The solvent was removed and the crude material waspurified by mass-triggered HPLC. ¹H NMR (400 MHz, MeOD) δ 8.57 (d,J=7.6, 1 H), 8.34 (s, 1H), 7.95 (d, J=8.3, 2H), 7.83 (d, J=8.4, 2H),7.73 (s, 4H), 7.61 (s, 1H), 6.85 (d, J=7.5, 1 H), 3.32 (s, 3H, obscuredby MeOD peak); MS m/z 457.0 (M+H)⁺.

Example 314-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide

Example 31 was prepared according to the procedure described for thesynthesis of Example 30 by replacing 4-cyanobenzene-1-sulfonyl chloridewith 4-fluorobenzene-1-sulfonyl chloride. ESI-LC/MS m/z 450.0 (M+H)+;r.t.=1.954.

Example 323-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 32 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 17 by replacing(1-methyl-1H-indazol-5-yl)boronic acid with (4-carbamoylphenyl)boronicacid. The reaction was purified by silica gel chromatography, elutingwith dichloromethane/ethyl acetate then 5% methanol/dichloromethane togive 32 as the desired product. ¹H NMR (400 MHz, DMSO) δ 8.87 (dd,J=0.6, 2.2, 1H), 8.72 (dd, J=0.7, 7.2, 1 H), 8.53 (s, 1H), 8.26 (dd,J=2.3, 8.6, 1 H), 8.03 (s, 1H), 8.00-7.91 (m, 3H), 7.67-7.57 (m, 3H),7.40 (s, 1H), 6.85 (dd, J=1.8, 7.2, 1 H), 3.53 (s, 3H). ESI-MS (m/z):[M+H]⁺ 398.1, RT 1.2637 min.

Example 33N-methyl-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 33 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile withN-methyl-5-(trifluoromethyl)pyridine-2-amine. The reaction was purifiedby mass-triggered HPLC to provide 33 as the desired product. ESI-MS(m/z): [M+H]⁺ 465.1, RT 2.0724 min.

Example 34N-methyl-N-(5-(methylsulfonyl)127yridine-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 33 was prepared according to the procedure described for thesynthesis of Example 1 by replacing 4-(methylamino)benzonitrile withN-methyl-5-(methylsulfonyl)pyridine-2-amine. The reaction was purifiedby silica gel chromatography, eluting with hexanes/EtOAc, followed bypurification by mass-triggered HPLC to provide 34 as the desiredproduct. ¹H NMR (400 MHz, MeOD) δ 8.89 (d, J=2.4, 1 H), 8.56 (d, J=7.2,1 H), 8.35 (s, 1H), 8.23 (dd, J=2.5, 8.6, 1 H), 7.91 (s, 1H), 7.75 (d,J=8.3, 2H), 7.66 (d, J=8.2, 2H), 7.56 (d, J=8.6, 1H), 6.94 (dd, J=1.8,7.3, 1H), 3.65 (s, 3H), 3.12 (s, 3H). ESI-MS (m/z): [M+H]⁺ 475.1, RT1.7860 min.

Example 35N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-amine

To a stirred solution of pyrazolopyridine (25 mg, 0.05 mmol) in dioxane(1.0 mL) was added 4N HCl in dioxane (1.0 mL). The reaction wasmonitored by LCMS and when the reaction was complete, the resultant HClsalt was filtered and dried to give 35. ESI-LC/MS m/z 386.1 (M+H)+;r.t.=2.167.

Example 36N-(4-fluorobenzyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-amine

NaH (5 mg, 0.08 mmol) was added to a solution of pyrazolopyridine (19mg, 0.05 mmol) and DMF (1.0 mL). MeI (0.020 mL, 0.06 mmol) was added andthe reaction was stirred for 4 h at room temperature. The reaction wasquenched by addition of H₂O. The solution was extracted with ethylacetate. The combined extracts were washed with brine, dried overanhydrous Na₂SO₄ and concentrated. The crude material was purified bysilica gel chromatography, eluting with ethyl acetate and hexanes. ¹HNMR (400 MHz, MeOD) δ 8.21 (d, J=8.7, 1H), 8.02 (s, 1H), 7.57 (q, J=8.7,4H), 7.19 (dd, J=5.4, 8.5, 2H), 6.98 (t, J=8.8, 2H), 6.78-6.63 (m, 2H),4.60 (s, 2H), 3.09 (s, 3H); MS m/z 400.2 (M+H)⁺.

Example 37N-methyl-6-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)nicotinamide

Example 37 was prepared according to the procedure described for thesynthesis of Example 28 by replacing 4-cyanobenzoyl chloride with6-(trifluoromethyl)nicotinoyl chloride. ¹H NMR (400 MHz, MeOD) δ 8.69(s, 1H), 8.48 (d, J=7.5, 1H), 8.20 (s, 1H), 7.97 (d, J=8.1, 1H), 7.63(dd, J=8.2, 24.5, 5H), 7.48 (d, J=8.1, 2H), 6.86 (dd, J=2.2, 7.4, 1H),3.48 (s, 3H). ESI-LC/MS m/z 465.1 (M+H)+; r.t.=1.696.

Example 38N-methyl-5-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)picolinamide

Example 38 was prepared according to the procedure described for thesynthesis of Example 28 by replacing 4-cyanobenzoyl chloride with5-(trifluoromethyl)picolinoyl chloride. ¹H NMR (400 MHz, CDCl3) δ 8.56(s, 1H), 8.35 (d, J=7.4, 1 H), 8.08 (s, 1H), 7.94 (d, J=6.9, 1H), 7.81(d, J=8.2, 1H), 7.59 (d, J=8.2, 2H), 7.40 (d, J=7.8, 2H), 7.32 (s, 1H),6.63 (s, 1H), 3.51 (s, 3H). ESI-LC/MS m/z 465.1 (M+H)+; r.t.=1.740.

Example 394-cyano-N-((tetrahydro-2H-pyran-4-yl)methyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide

Example 39 was prepared according to the procedure described for thesynthesis of Example 28. ¹H NMR (400 MHz, CDCl3) δ 8.35 (d, J=7.4, 1H),8.09 (s, 1H), 7.61 (d, J=8.1, 2H), 7.52 (d, J=8.4, 2H), 7.43 (d, J=8.5,2H), 7.29 (d, J=8.1, 2H), 7.17 (s, 1H), 6.50 (dd, J=2.3, 7.4, 1 H),3.97-3.81 (m, 4H), 3.25 (dd, J=9.8, 11.7, 2H), 1.96 (d, J=13.1, 1H),1.55 (d, J=18.6, 2H), 1.45-1.29 (m, 2H). ESI-LC/MS m/z 505.1 (M+H)+;r.t.=1.689.

Example 40N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of aryl bromide (I-8) (1.0 equiv.),(1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid (1.5 equiv.), K₂HPO₄ (2.5equiv.), and Pd(dppf)Cl2 (0.05-0.15 equiv.) in THF/water was allowed toheat at 80° C. overnight. The solvent was removed and the crude residuewas purified by silica gel chromatography, eluting with hexanes/EtOAc,then 5% MeOH/CH₂Cl₂ gave the desired product. ¹H NMR (400 MHz, DMSO) δ11.76 (s, 1H), 8.64 (dd, J=0.7, 7.2, 1H), 8.39 (s, 1H), 8.33 (d, J=2.1,1H), 7.88 (d, J=2.0, 1H), 7.84 (d, J=8.6, 2H), 7.79 (s, 1H), 7.59-7.50(m, 3H), 6.79 (dd, J=1.8, 7.2, 1H), 6.53 (dd, J=1.8, 3.4, 1 H), 3.46 (s,3H). ESI-MS (m/z): [M+H]⁺ 393.1, RT 1.1533 min.

Example 413-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 41 was prepared according to the procedure described for thesynthesis of Example 40 by replacing(1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid with(6-aminopyridin-3-yl)boronic acid. The reaction was purified by silicagel chromatography, eluting with hexanes/EtOAc, then 5% MeOH/CH₂Cl₂,followed by purification by mass-triggered HPLC and a NaHCO₃/EtOAcworkup gave the desired product. ¹H NMR (400 MHz, MeOD) δ 8.43 (dd,J=0.7, 7.3, 1H), 8.12 (s, 1H), 7.93 (d, J=1.6, 1H), 7.72 (d, J=8.6, 2H),7.68 (s, 1H), 7.50 (dd, J=2.4, 8.6, 1 H), 7.46 (d, J=8.6, 2H), 6.83 (dd,J=1.8, 7.3, 1 H), 6.69 (d, J=8.6, 1 H), 3.54 (s, 3H). ESI-MS (m/z):[M+H]⁺ 369.1, RT 0.8592 min.

Example 423-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of aryl bromide (I-8) (1.0 equiv.), (4-aminophenyl)boronicacid (1.5 equiv.), K₂HPO₄ (2.5 equiv.), and Pd(dppf)Cl2 (0.05-0.15equiv.) in THF/water was allowed to heat at 110° C. overnight. Thesolvent was removed and the crude residue was by silica gelchromatography, eluting with hexanes/EtOAc gave the desired product.ESI-MS (m/z): [M+H]⁺ 368.1, RT 1.0446 min.

Example 433-(4-(2-aminoacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

A solution of Example 42 (1.0 equiv.) in CH₂Cl₂ (˜0.1 M) was treatedwith 2-((tert-butoxycarbonyl)amino)acetic acid (1.2 equiv.), followed byHATU (1.1 equiv (2.5 equiv.). The resulting mixture was allowed to stirat rt for two hours, and then was filtered and treated with one volumeof TFA. The resulting solution was allowed to stir at rt for 30 minutes,and the solvents were removed under reduced pressure. The residue waspurified by mass-triggered HPLC to provide the desired product. ESI-MS(m/z): [M+H]⁺ 425.1, RT 1.1033 min.

Example 44(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 44 was prepared according to the procedure described for thesynthesis of Example 43 by replacing2-((tert-butoxycarbonyl)amino)acetic acid with(R)-2-((tert-butoxycarbonyl)amino)propanoic acid. ESI-MS (m/z): [M+H]⁺439.2, RT 1.0950 min.

Example 45(S)-3-(4-(2-amino-3-methylbutanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 45 was prepared according to the procedure described for thesynthesis of Example 43 by replacing2-((tert-butoxycarbonyl)amino)acetic acid with(S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid. ESI-LC/MS m/z467.2 (M+H)+; RT=1.230.

Example 46(S)-3-(4-(2-amino-2-cyclohexylacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 46 was prepared according to the procedure described for thesynthesis of Example 43 by replacing2-((tert-butoxycarbonyl)amino)acetic acid with(S)-2-((tert-butoxycarbonyl)amino)-2-cyclohexylacetic acid. ESI-MS(m/z): [M+H]⁺ 507.2, RT 1.4154 min.

Example 473-(4-fluorophenyl)-1-methyl-1-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)urea

NaH (8 mg, 0.15 mmol) was added to a solution of pyrazolopyridine (30mg, 0.10 mmol) and DMF (2.0 mL). The reaction was stirred at roomtemperature for 15 minutes. The isocyanate was added and the reactionstirred at room temperature for an additional 4 hours. The reaction wasquenched with water and extracted with ethyl acetate. The combinedorganic extracts were washed with brine and dried over anhydrous Na₂SO₄.The solvent was removed and the material was purified by silica gelchromatography eluting with ethyl acetate and hexanes. ¹H NMR (400 MHz,CDCl3) δ 8.49 (d, J=7.3, 1H), 8.16 (s, 1H), 7.61 (dd, J=8.5, 25.1, 5H),7.19 (s, 3H), 6.89 (t, J=7.5, 2H), 6.76 (d, J=7.3, 1 H), 6.31 (s, 1H),3.33 (s, 3H).

Example 486-(1,1-difluoroethyl)-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide

To a solution of 6-(1,1-difluoroethyl)nicotinic acid (28 mg, 0.15 mmol)in dichloromethane (1.00 mL) was added triethyl amine (0.042 mL, 0.30mmml) and a catalytic amount of DMF. The reaction was cooled to 0° C.Oxallyl chloride was added dropwise and the reaction mixture was stirredfor 30 minutes. The solvent was removed and the solid was dried undervacuum for 15 minutes. To the crude acid chloride was addeddichloromethane (1.00 mL) and triethylamine (0.042 mL, 0.30 mmol)followed by the amine (29 mg, 0.10 mmol) at 0° C. The reaction wasallowed to warm to room temperature and stir for two hours. The reactionwas quenched with water, extracted with dichloromethane, washed withbrine, dried over Na₂SO₄ and concentrated. The reaction was purified bysilica gel chromatography, eluting with ethyl acetate and hexanes. ¹HNMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.46 (d, J=7.4, 1H), 8.17 (s, 1H),7.92 (d, J=8.1, 1H), 7.69 (d, J=8.1, 2H), 7.63 (d, J=8.1, 1H), 7.41 (d,J=7.9, 2H), 7.35 (s, 1H), 6.64 (d, J=7.3, 1H), 3.60 (s, 3H). ESI-LC/MSm/z 461.1 (M+H)+; r.t.=1.993.

Example 496-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide

Example 49 was prepared according to the procedure described for thesynthesis of Example 48 by replacing 6-(1,1-difluoroethyl)nicotinic acidwith 6-cyclopropylnicotinic acid. ESI-LC/MS m/z 437.1 (M+H)+; RT=1.640.

Example 504-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide

Example 50 was prepared according to the procedure described for thesynthesis of Example 48 by replacing 6-(1,1-difluoroethyl)nicotinic acidwith 4-cyclopropylbenzoic acid. ESI-LC/MS m/z 436.0 (M+H)+; RT=2.408.

Example 515-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide

Example 51 was prepared according to the procedure described for thesynthesis of Example 48 by replacing 6-(1,1-difluoroethyl)nicotinic acidwith 5-fluoropicolinic acid. ¹H NMR (400 MHz, CDCl3) δ 7.71 (d, J=7.4, 1H), 7.48 (s, 1H), 7.46 (s, 1H), 7.00 (s, 1H), 6.95-6.78 (m, 6H), 6.08(d, J=7.4, 1H), 2.80 (d, J=38.0, 3H). ESI-LC/MS m/z 415.0 (M+H)+;r.t.=2.158.

Example 52N-methyl-4-(methylsulfonyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide

Example 52 was prepared according to the procedure described for thesynthesis of Example 48 by replacing 6-(1,1-difluoroethyl)nicotinic acidwith 4-(methylsulfonyl)benzoic acid. ESI-LC/MS m/z 474.1 (M+H)+;RT=2.071

Example 53N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 53 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 32 by replacing(4-carbamoylphenyl)boronic acid with(1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid. Purification by silica gelchromatography, eluting with hexanes/EtOAc, and then 5% EtOH/EtOAc gavethe desired product. ¹H NMR (400 MHz, DMSO) δ 11.76 (s, 1H), 8.88 (dd,J=0.6, 2.3, 1 H), 8.70 (dd, J=0.8, 7.2, 1 H), 8.44 (s, 1H), 8.38 (d,J=2.1, 1 H), 8.26 (dd, J=2.3, 8.6, 1 H), 7.99 (d, J=2.0, 1 H), 7.91 (s,1H), 7.60 (dd, J=0.5, 8.6, 1H), 7.57-7.50 (m, 1H), 6.82 (dd, J=1.8, 7.2,1H), 6.51 (dd, J=1.8, 3.4, 1 H), 3.53 (s, 3H). ESI-MS (m/z): [M+H]⁺394.0, RT 1.4237 min.

Example 543-(6-aminopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 54 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 32 by replacing(4-carbamoylphenyl)boronic acid with (6-aminopyridin-3-yl)boronic acid.Purification by silica gel chromatography, eluting with hexanes/EtOAc,and then 10% EtOH/EtOAc gave the desired product. ¹H NMR (400 MHz, DMSO)δ 8.84 (d, J=2.3, 1 H), 8.63 (dd, J=0.7, 7.3, 1 H), 8.29 (s, 1H), 8.23(dd, J=2.3, 8.6, 1 H), 8.09 (d, J=2.2, 1 H), 7.86-7.80 (m, 1H), 7.58 (d,J=8.6, 1 H), 7.54 (dd, J=2.5, 8.5, 1 H), 6.75 (dd, J=1.8, 7.2, 1 H),6.54 (d, J=8.6, 1 H), 6.05 (s, 2H), 3.52 (s, 3H). ESI-MS (m/z): [M+H]⁺370.0, RT 1.2469 min.

Example 554-chloro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide

Example 25 was prepared according to the procedure described for thesynthesis of Example 28 by replacing 4-cyanobenzoyl chloride with4-fluorobenzoyl chloride. ¹H NMR (400 MHz, CDCl3) δ 8.33 (d, J=7.5, 1H), 8.07 (s, 1H), 7.58 (d, J=8.2, 2H), 7.42-7.26 (m, 4H), 7.26-7.12 (m,3H), 6.53 (dd, J=2.3, 7.4, 1 H), 3.47 (s, 3H). ESI-LC/MS m/z 430.0(M+H)+; r.t.=2.376.

Example 56N-(3-(4-carbamoylphenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylbenzamide

Example 56 was prepared from intermediate I-54 according to theprocedure described for the synthesis of Example 17 by replacing(1-methyl-1H-indazol-5-yl)boronic acid with (4-carbamoylphenyl)boronicacid. ESI-LC/MS m/z 389.1 (M+H)+; r.t.=1.603.

Example 574-fluoro-N-methyl-N-(3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide

Example 57 was prepared from intermediate I-54 according to theprocedure described for the synthesis of Example 17 by replacing(1-methyl-1H-indazol-5-yl)boronic acid with(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)boronic acid. ¹H NMR(400 MHz, MeOD) δ 8.53 (d, J=7.4, 1 H), 8.29 (s, 1H), 7.85 (d, J=8.4,2H), 7.66-7.45 (m, 5H), 7.07 (t, J=8.8, 2H), 6.90 (dd, J=2.3, 7.5, 1H),3.56 (s, 3H), 3.12 (s, 3H). ESI-LC/MS m/z 459.0 (M+H)+; r.t.=1.708.

Example 58N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 58 was prepared from intermediate I-66 according to theprocedure described for the synthesis of Example 17 by replacing(1-methyl-1H-indazol-5-yl)boronic acid with(1H-pyrrolo[2,3-b]pyridin-5-yl)boronic acid. ESI-MS (m/z): [M+H]⁺ 447.0,RT 1.3983 min. ESI-LC/MS m/z 447.0 (M+H)+; r.t.=1.398.

Example 59N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 29 was prepared according to the procedure described for thesynthesis of Example 25 by replacing2-chloro-5-(trifluoromethyl)pyridine with 2-chloro-5-methylpyridine. Thereaction was purified by mass-triggered HPLC to provide the desiredproduct. ESI-MS (m/z): [M+H]⁺ 369.1, RT 1.3394 min.

Example 60N-(5-cyanopyridin-2-yl)-3-(5-methoxypyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 60 was prepared according to the procedure described for thesynthesis of Example 25 by replacing2-chloro-5-(trifluoromethyl)pyridine with 2-chloro-5-methoxypyridine.The reaction was purified by mass-triggered HPLC to provide the desiredproduct. ESI-MS (m/z): [M+H]⁺ 385.1, RT 1.5073 min.

Example 613-(5-carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 61 was prepared according to the procedure described for thesynthesis of Example 25 by replacing2-chloro-5-(trifluoromethyl)pyridine with 6-chloronicotinamide. Thereaction was purified by mass-triggered HPLC to provide the desiredproduct. ESI-MS (m/z): [M+H]⁺ 398.1, RT 1.4232 min.

Example 623-(4-carbamoylphenyl)-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 62 was prepared according to the procedure described for thesynthesis of Example 32. The reaction was purified by mass-triggeredHPLC to provide the desired product. ESI-MS (m/z): [M+H]⁺ 440.0, RT1.7179 min.

Example 633-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 63 was prepared according to the procedure described for thesynthesis of Example 32. The reaction was purified by mass-triggeredHPLC to provide the desired product. ESI-MS (m/z): [M+H]⁺ 386.1, RT1.4742 min.

Example 64N-(4-fluorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of aryl bromide (I-54, 1.0 equiv.),(4-(methylcarbamoyl)phenyl)boronic acid (2.0 equiv.), KF (2.0 equiv.),and Pd(PPh)₃ (0.05 equiv.) in 1,4-dioxane/DME/water was allowed to heatat 100° C. in a microwave reactor for 5 minutes. Following extraction ofthe reaction mixture with ethyl acetate, the solvent was removed underreduced pressure and the residue was purified by silica gelchromatography, eluting with ethyl acetate and hexanes to give 64 as thedesired product. ¹H NMR (400 MHz, Methanol-d₄) δδ ppm 8.46 (d, J=8.00Hz, 1H) 8.26 (s, 1H), 7.89 (d, J=8.00 Hz, 2H) 7.76 (s, 1H), 7.49 (d,J=8.00 Hz, 2H) 7.32-7.35 (m, 2H) 7.12 (t, J=8.00 Hz, 2H) 6.91 (d, J=8.00Hz, 1H) 3.50 (s, 3H) 2.96 (s, 3H); ESI-MS (m/z): [M+H]⁺ 403.

Example 654-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide

Example 65 was prepared from intermediate I-19 according to generalSuzuki procedure E. A mixture of aryl bromide (I-19, 1.0 equiv.),(4-carbamoylphenyl)boronic acid (1.5 equiv.), 2 M aq KF (3 equiv.), andPd₂(dba)₃ (0.1 equiv.), P(o-tolyl)₃(0.1 equiv.) in toluene:ethanol (7:3)was degassed and heated to 90° C. for 4 h. The crude product waspurified by silica gel chromatography, eluting with ethyl acetate andhexanes to give 65 as the desired product. ¹H NMR (400 MHz, DMSO-d₆): δ8.65 (d, J=7.50 Hz, 1H), 8.43 (s, 1H), 7.97 (d, J=8.3 Hz, 4H), 7.75 (d,J=7.9 Hz, 3H), 7.42-7.40 (m, 1H), 7.38 (d, J=5.0 Hz, 1H), 6.75 (d,J=7.10 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H), 6.14-6.11 (m, 1H), 2.70 (s, 3H),2.15 (s, 3H), 1.57 (d, J=7.9 Hz, 3H); ESI-MS (m/z): [M+H]⁺ 386.1.

Example 664-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide

Example 66 was prepared from intermediate I-67 according to generalSuzuki procedure E. A mixture of aryl bromide (I-67, 1.0 equiv.),(4-carbamoylphenyl)boronic acid (1.5 equiv.), 2 M aq KF (3 equiv.), andPd₂(dba)₃ (0.1 equiv.), P(o-tolyl)₃(0.1 equiv.) in toluene:ethanol (7:3)was degassed and heated to 90° C. for 7 h. The crude compound waspurified by silica gel chromatography, eluting with 2% MeOH/DCM to give4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide66 as the desired product (37%). ¹H NMR (400 MHz, DMSO-d₆). δ 8.69 (d,J=7.50 Hz, 1H), 8.47 (s, 1H), 8.01 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.90(s, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.37 (br. s, 1H), 7.02 (dd, J=3.1, 9.4Hz, 1H), 6.96-6.92 (m, 1H), 6.82 (dd, J=1.8, 7.3 Hz, 1H), 6.73 (dt,J=3.0, 8.6, Hz, 1H), 6.16-6.21 (m, 1H), 4.80 (m, 2H), 1.85 (d, J=7.0 Hz,3H); ESI-LC/MS (Method 1) (m/z): [M+H]⁺ 431.

Example 67N-(4-cyanophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 67 was prepared from intermediate I-8 according to generalSuzuki procedure F. A mixture of aryl bromide (I-8) (1.0 equiv.),(4-(methylcarbamoyl)phenyl)boronic acid (1.2 equiv.), Na₂CO₃ (2.0equiv.), and Pd(PPh₃)₄ (0.1 equiv.) in dioxane was allowed to heat at100° C. in microwave reactor for 40 minutes. The reaction was filteredover celite and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel chromatography, eluting withhexanes/EtOAc to give 67 as the desired product. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.66 (d, J=7.28 Hz, 1H) 8.48 (s, 2H) 7.91 (d, J=8.03 Hz,2H) 7.81-7.88 (m, 3H) 7.54 (t, J=7.78 Hz, 4H) 6.83 (d, J=7.53 Hz, 1H)3.46 (s, 3H) 2.82 (d, J=4.02 Hz, 3H). ESI-MS (m/z): [M+H]⁺ 410.

Example 68N-(4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)phenyl)acetamide

Example 68 was prepared from intermediate I-19 according to theprocedure described for the synthesis of Example 65 (general Suzukiprocedure E) by replacing (4-carbamoylphenyl)boronic acid with(4-acetamidophenyl)boronic acid. The crude product was purified bysilica gel chromatography, eluting with ethyl acetate and hexanes togive 68 as the desired product. ¹H NMR (400 MHz, DMSO-d₆) δ 10.01 (s,1H), 8.60 (d, J=7.5 Hz, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 7.66-7.68 (m,3H), 7.58 (d, J=8.6 Hz, 2H), 7.40 (d, J=7.0 Hz, 1H), 6.68 (d, J=7.5 Hz,1H), 6.63 (d, J=8.6 Hz, 1H), 6.11 (d, J=6.5 Hz, 1H), 2.7 (s, 3H), 2.1(s, 3H), 2.0 (s, 3H), 1.55 (d, J=7.0 Hz, 3H); ESI-LC/MS (Method 2)(m/z): [M+H]⁺ 400.

Example 693-(4-acetamidophenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 69 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 65 (general Suzuki procedure E)by replacing (4-carbamoylphenyl)boronic acid with(4-acetamidophenyl)boronic acid. The crude product was purified bycolumn chromatography over silica gel (MeOH/CH₂Cl₂, 0-2% MeOH) to give68 as the desired product. ¹H NMR (400 MHz, DMSO-d₆): δ 10.0 (s, 1H),8.85 (m, 1H), 8.66 (d, J=7.3 Hz, 1H), 8.38 (s, 1H), 8.24 (dd, J=2.1, 8.5Hz, 1H), 7.93 (s, 1H), 7.66 (d, J=8.6 Hz), 7.61 (d, J=8.6 Hz, 3H), 7.47(d, J=8.6 Hz, 2H), 6.78 (dd, J=1.6, 7.3 Hz, 1H), 3.5 (s, 3H), 2.06 (s,3H); ESI-MS (method 2) (m/z): [M+H]⁺ 411.21.

Example 714-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide

Example 71 was prepared from intermediate I-20 according to theprocedure described for the synthesis of Example 65 (general Suzukiprocedure E). The crude product was purified by column chromatographyover silica gel (MeOH/Chloroform, 0-5% MeOH). to give 71 as the desiredproduct. ¹H NMR (400 MHz, DMSO-d₆ at 80° C.): δ 9.75 (s, 1H), 8.76 (d,J=7.0 Hz, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.57-7.68 (m, 4H), 7.28-7.32(m, 1H), 6.97-6.99 (m, 1H), 6.84-6.87 (m, 1H), 6.68-6.72 (m, 1H), 4.6(bs, 1H), 4.22-4.4 (m, 2H), 2.06 (s, 3H), 1.195 (d, J=6.6 Hz, 3H);ESI-MS (method 2) (m/z): [M+H]⁺ 445.

Example 724-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide

Example 72 was prepared from intermediate I-24 according to theprocedure described for the synthesis of Example 65 (general Suzukiprocedure E). The crude product was purified by silica gelchromatography (MeOH/Chloroform, 0-5% MeOH) to give 72 as the desiredproduct. ¹H NMR (400 MHz, DMSO-d6 at 80° C.): δ 8.73 (d, J=7.0 Hz, 1H),8.47 (s, 1H), 8.10 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.3 Hz,2H), 7.35-7.31 (m, 3H), 6.99-7.02 (m, 1H), 6.78-6.82 (m, 1H), 6.59-6.65(m, 1H), 4.63 (d, J=6.2 Hz, 1H), 4.36-4.39 (m, 1H), 4.21-4.24 (m, 1H),1.22 (d, J=7.0 Hz, 3H); ESI-MS (method 2) (m/z): [M+H]⁺ 431.

Example 734-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide

Example 73 was prepared from intermediate I-20 according to theprocedure described for the synthesis of Example 65 (general Suzukiprocedure E) by replacing (4-carbamoylphenyl)boronic acid with(4-(methylcarbamoyl)phenyl)boronic acid. The residue was purified columnchromatography over silica gel (MeOH/Chloroform, 0-2% MeOH) to give 73as the desired product. ¹H NMR (400 MHz, CDCl₃): δ 9.99 (s, 1H), 8.77(d, J=7.03 Hz, 1H), 8.40 (d, J=1.31 Hz, 1H), 8.10 (s, 1H), 7.57-7.67 (m,5H), 6.99-7.01 (m, 1H), 6.83-6.85 (m, 1H), 6.69 (m, 1H), 4.36 (m, 2H),3.94 (m, 2H), 2.05 (s, 3H); ESI-MS (method 1) (m/z): [M+H]⁺ 431.15.

Example 744-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide

Example 74 was prepared from intermediate I-24 according to theprocedure described for the synthesis of Example 65 (general Suzukiprocedure E) by replacing (4-carbamoylphenyl)boronic acid with(4-(methylcarbamoyl)phenyl)boronic acid. The crude product was purifiedby column chromatography over silica gel (MeOH/Chloroform, 0-5% MeOH) togive 74 as the desired product. ¹H NMR (400 MHz, DMSO-d6 at 80° C.): δ9.75 (s, 1H), 8.76 (d, J=7.0 Hz, 1H), 8.40 (s, 1H), 8.11 (s, 1H),7.57-7.68 (m, 4H), 7.28-7.32 (m, 1H), 6.97-6.99 (m, 1H), 6.84-6.87 (m,1H), 6.68-6.72 (m, 1H), 4.6 (bs, 1H), 4.22-4.4 (m, 2H), 2.06 (s, 3H),1.195 (d, J=6.6 Hz, 3H); ESI-MS (m/z): [M+H]⁺ 445.

Example 75N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 75 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 65 (general Suzuki procedure E)by replacing (4-carbamoylphenyl)boronic acid with(4-(methylcarbamoyl)phenyl)boronic acid. The crude product was purifiedby column chromatography over silica gel (MeOH/Chloroform, 0-2% MeOH) togive 74 as the desired product. ¹H NMR (400 MHz, DMSO-d₆): δ 8.86 (d,J=1.6 Hz, 1H), 8.71 (dd, J=0.7, 7.3 Hz, 1H), [8.53 (s), 8.49 (d, J=4.6Hz) 2H], 8.26 (dd, J=2.3, 8.7 Hz, 1H), [7.99 (d, J=0.7 Hz), 7.92 (d,J=8.5 Hz) 3H], 7.65 (m, 3H), 6.84 (dd, J=1.9, 7.3 Hz, 1H), 3.53 (s, 3H),2.81 (d, J=4.6 Hz, 3H) ESI-MS (Method 2) (m/z): [M+H]⁺ 411.2.

The difference with Method 2 used here is Gradient: 0.4 mL/minute,initial 20% B ramp to 80% B over 2.0 minutes, (instead of ramp to 90%over 2.0 minutes in Method 2), then hold until 4.0 minutes, return to20% B at 4.1 minutes until end of run.

Example 76N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 76 was prepared from intermediate I-26 according to theprocedure described for the synthesis of Example 64 by replacing(4-carbamoylphenyl)boronic acid with (4-(methylcarbamoyl)phenyl)boronicacid. The residue was purified by silica gel chromatography, elutingwith ethyl acetate and hexanes to give 76 as the desired product. ¹H NMR(400 MHz, METHANOL-d₄) 8.66 (d, J=7.28 Hz, 1H) 8.52 (s, 1H) 8.38 (s, 1H)7.93-8.00 (m, 3H) 7.75 (d, J=8.78 Hz, 2H) 7.40 (dd, J=7.28, 1.76 Hz, 1H)7.00 (dd, J=9.91, 1.88 Hz, 1H) 6.38 (d, J=10.29 Hz, 1H) 4.52-4.62 (m,1H) 4.46 (d, J=1.00 Hz, 2H) 4.32 (t, J=11.42 Hz, 1H) 4.14 (dd, J=11.92,7.15 Hz, 1H) 2.96 (s, 3H); ESI-MS (m/z): [M+H]⁺ 443.

Example 77N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Example 77 was prepared from intermediate I-27 according to theprocedure described for the synthesis of Example 65 (general Suzukiprocedure E). The residue was purified by preparative TLC (silica gel GF254) using 3% methanol in chloroform as eluant to give 77 as the desiredproduct. ¹H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.63 (d, J=7.5 Hz, 1H),8.47 (s, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.99 (d, J=8.3 Hz,2H), 7.75 (s, 1H), 7.61 (s, 1H), 7.51 (d, J=7.9 Hz, 2H), 7.39 (s, 1H),7.34 (s, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.68 (d, J=7.0 Hz, 1H), 6.14 (s,1H), 5.75 (m, 1H), 4.85-4.86 (m, 1H), 4.47-4.48 (m, 1H), 1.35 (d, J=7.0Hz, 3H); ESI-LC/MS (Method 2) (m/z): [M+H]⁺ 491.3, RT 1.32 min.

The difference with Method-2 used here is Gradient: 0.4 mL/minute,initial 20% B ramp to 80% B over 2.0 minutes, (instead of ramp to 90%over 2.0 minutes in Method 2) then hold until 4.0 minutes, return to 20%B at 4.1 minutes until end of run.

Example 793-(6-amino-5-fluoropyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of3-bromo-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(I-8; 400 mg, 1.10 mmol 1.0 eq),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-37, 550 mg, 2.20 mmol 2.0 eq) and 1N Na₂CO₃ solution (4.0 mL) in1,4-dioxane (10 mL) was degassed with argon gas for 10 min.Subsequently, tetrakis(triphenyl phosphine)-palladium(0) (250 mg, 0.22mmol 0.2 eq) was added and the reaction mixture was stirred in a sealedtube at 100° C. for 2.5 h (cf. general Suzuki Procedure F). The solventwas removed under reduced pressure. Purification by silica gelchromatography, eluting with 5% MeOH/CH₂Cl₂ provided 79 as the desiredproduct (37%). ¹H NMR (400 MHz, DMSO) δ 8.58 (d, J=7.0 Hz, 1H), 8.31 (s,1H), 7.91 (s, 1H), 7.78 (d, J=8.8 Hz, 3H), 7.53 (d, J=8.30 Hz, 2H), 7.46(d, J=12.3 Hz, 1H), 6.74 (d, J=7.0 Hz, 1H), 6.30 (s, 2H), 3.45 (s, 3H);ESI-LC/MS (m/z): [M+H]⁺ 387.10, RT 1.71 min.

Example 803-(4-amino-3,5-dimethylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 80 was prepared from intermediate I-8 according to the proceduredescribed for the synthesis of Example 79 by replacing3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-37) with2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(I-38). Purification by silica gel chromatography, eluting with 5%MeOH/CH₂Cl₂ provided 80 as the desired product (34%) ¹H NMR (400 MHz,DMSO) δ 8.54 (d, J=7.10 Hz, 1H), 8.15 (s, 1H) I-37, 7.81 (d, J=8.40 Hz,2H), 7.65 (s, 1H), 7.52 (d, J=8.3 Hz, 2H), 6.87 (s, 2H), 6.72 (d, J=7.40Hz, 1H), 4.65 (s, 2H), 3.45 (s, 3H), 2.14 (s, 6H); ESI-LC/MS (m/z):[M+H]⁺ 396.16, RT 1.51 min.

Example 813-(6-amino-5-methylpyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 81 was prepared from intermediate I-8 according to the proceduredescribed for the synthesis of Example 79 by replacing3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-37) with3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-39). Purification by silica gel chromatography, eluting with 5%MeOH/CH₂Cl₂ provided 81 as the desired product (44%). ¹H NMR (400 MHz,DMSO) δ 8.56 (d, J=7.50 Hz, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.79 (d,J=8.30 Hz, 1H), 7.71 (s, 1H), 7.52 (d, J=8.30 Hz, 1H), 7.31 (s, 1H),6.72 (d, J=7.50 Hz, 1H), 5.80 (s, 2H), 3.44 (s, 3H), 2.11 (s, 3H);ESI-LC/MS (m/z): [M+H]⁺ 383.07, RT 1.66 min.

Example 823-(4-carbamoylphenyl)-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 82 was prepared from intermediate I-33 according to theprocedure described for the synthesis of Example 65 (general Suzukiprocedure E). The residue was purified by silica gel chromatography,eluting with 3% MeOH/CHCl₃ to give 82 as the desired product (30%). ¹HNMR (400 MHz, DMSO) δ 8.68 (d, J=6.6 Hz, 1H), 8.38 (s, 1H), 7.97-8.01(m, 3H), 7.76-7.78 (m, 2H), 6.97 (m, 1H), 4.42 & 3.62 (two broadsignals, 1H), 3.30 (m, 3H), 1.50-2.59 (m, 8H); ESI-LC/MS (m/z): [M+H]⁺402.14, RT 1.02 min.

Example 833-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 83 was prepared from intermediate I-8 according to the proceduredescribed for the synthesis of Example 79 by replacing3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-37) with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (I-40).Purification by silica gel chromatography, eluting with 5% MeOH/CH₂Cl₂provided 83 as the desired product (27%). ¹H NMR (400 MHz, DMSO) δ 8.59(d, J=7.50 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 1H), 7.77 (s, 3H), 7.52 (d,J=7.90 Hz, 2H), 6.73 (s, 3H), 3.30 (s, 3H); ESI-LC/MS (m/z): [M+H]⁺370.10, RT 0.93 min.

Example 843-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 84 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 79 by replacing3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-37) with5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoro-methyl)pyridin-2-amine(I-41). Purification by silica gel chromatography, eluting with 1%MeOH/CHCl₃ gave the desired product (41%). ¹H NMR (400 MHz, DMSO) δ 8.82(d, J=1.2 Hz, 1H), 8.64 (d, J=7.1 Hz, 1H), 8.39-8.41 (m, 2H), 8.21 (dd,J=2.2, 6.1 Hz, 1H), 7.80-7.86 (m, 2H), 7.58 (d, J=8.7 Hz, 1H), 6.78-6.81(m, 1H), 6.52-6.56 (m, 2H), 3.52 (s, 1H); ESI-LC/MS (m/z): [M+H]⁺438.08, RT 1.37 min.

Example 853-(6-amino-5-cyanopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 85 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 79 by replacing3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-37) with2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotino-nitrile(I-42). Purification by silica gel chromatography, eluting with 5%MeOH/CH₂Cl₂ provided 85 the desired product (23%). ¹H NMR (400 MHz,DMSO) δ 8.83 (d, J=1.70 Hz, 1H), 8.66 (d, J=7.10 Hz, 1H), 8.45 (d,J=2.60 Hz, 1H), 8.40 (s, 1H), 8.21 (dd, J=2.2, 6.6 Hz, 1H), 8.06 (d,J=2.10 Hz, 1H), 7.98 (s, 1H), 7.60 (d, J=8.70 Hz, 1H), 7.00 (s, 2H),6.78 (d, J=8.8 Hz, 1H), 3.52 (s, 3H); ESI-LC/MS (m/z): [M+H]⁺ 395.09, RT1.45 min.

Example 863-(6-amino-5-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 86 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 79 by replacing3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-37) with3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-43). Purification by preparative TLC provided 86 the desired product(41%). ¹H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.65 (d, J=7.50 Hz, 1H),8.36 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.11 (s, 1H), 7.79 (s, 1H), 7.65(s, 1H), 7.58 (d, J=8.8 Hz, 1H), 6.79 (d, J=7.0 Hz, 1H), 6.40 (s, 2H),3.52 (s, 3H); ESI-LC/MS (m/z): [M+H]⁺ 404.09, RT 1.27 min.

Example 873-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 87 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 79 by replacing3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-37) with2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide(I-44). Purification by preparative TLC provided 87 as the desiredproduct (10%). ¹H NMR (400 MHz, DMSO) δ 8.81 (d, J=2.2 Hz, 1H), 8.64 (d,J=7.0 Hz, 1H), 8.35 (s, 1H), 8.20 (d, J=2.2 Hz, 2H), 8.17 (d, J=2.20 Hz,1H), 7.80 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.48 (d, J=2.2 Hz, 1H), 6.76(dd, J=1.7, 7.0 Hz, 1H), 3.52 (s, 3H), 2.97 (s, 6H); ESI-LC/MS (m/z):[M+H]⁺ 441.11, RT 1.54 min.

Example 883-(6-amino-5-methoxypyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 88 was prepared from intermediate I-9 according to the proceduredescribed for the synthesis of Example 79 by replacing3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(I-37) with3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine(I-45). Purification by silica gel chromatography, eluting with 5%MeOH/CH₂Cl₂ provided 88 as the desired product (36%). ¹H NMR (400 MHz,DMSO) δ 8.78 (s, 1H), 8.62 (d, J=7.40 Hz, 1H), 8.33 (s, 1H), 8.28-8.20(dd, J=2.2, 6.60 Hz, 1H), 7.86 (s, 1H), 7.66 (s, 1H), 7.58 (d, J=8.8 Hz,1H), 7.16 (s, 1H), 6.77 (d, J=5.70 Hz, 1H), 5.79 (s, 2H), 3.84 (s, 3H),3.52 (s, 3H); ESI-LC/MS (m/z): [M+H]⁺ 400.06, RT 1.11 min.

Example 893-(4-carbamoylphenyl)-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Example 89 was prepared from intermediate I-15 according to theprocedure described for the synthesis of Example 65 (general Suzukiprocedure E). The crude product was purified by preparative TLC to give89 as the desired product. ¹H NMR (400 MHz, DMSO) δ 10.02 (s, 1H), 8.62(d, J=7.0 Hz, 1H), 8.44 (s, 1H), 8.02-7.86 (m, 3H), 7.86 (s, 2H), 7.74(d, J=5.2 Hz, 1H), 7.63 (s, 1H), 7.43-7.35 (m, 3H), 6.81 (d, J=7.0 Hz,1H), 3.80 (s, 3H); ESI-LC/MS (m/z): [M+H]⁺ 433.2, RT 4.75 min.

Example 90N-(5-Cyanopyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

A solution of3-bromo-N-(5-cyanopyridin-2-yl)-N-ethylpyrazolo[1,5-a]pyridine-5-carboxamideI-69 (25.0 g, 67.53 mmol), 4-(N-methylaminocarbonyl)phenylboronic acid(18.19 g, 101.62 mmol) and NaHCO₃ (11.24 g, 135.5 mmol) inacetonitrile:water (9:1) (500 mL) was degassed with argon for about 30min. To this mixture were added Pd₂(dba)₃.CHCl₃ adduct (7.0 g, 6.77mmol), X-phos (9.69 g, 20.32 mmol) under argon atmosphere. The resultingreaction mixture was maintained at 100° C. for 2 h then allowed to rtand filtered through celite. The filtrate was partitioned between water(2.5 L) and ethyl acetate (2.5 L). The ethyl acetate layer was washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. This crudecompound was purified by column chromatography over silica gel (100-200mesh) using a solvent gradient of 1% methanol in dichloromethane toobtained title compound. This compound was re-precipitation by using amixture of dichloromethane and n-pentane to give 17.2 g (60%) ofN-(5-cyanopyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide90 as a yellow color solid. H-NMR (DMSO-d₆): δ 8.87 (d, J=2.0 Hz, 1H),8.67 (d, J=7.6 Hz, 1H), 8.50 (s, 1H), 8.44-8.45 (m, 1H), 8.23 (dd,J=2.0, 8.0 Hz, 1H), 7.91-7.93 (m, 3H), 7.60 (d, J=8.8 Hz, 2H), 7.52 (d,J=8.4 Hz, 1H), 6.77 (dd, J=1.6, 7.2 Hz, 1H), 4.11 (q, J=6.8, 6.8 Hz,2H), 2.81 (d, J=4.4 Hz, 3H), 1.20 (t, J=7.2 Hz, 3H). ESI-LC/MS: m/z 425(M+H); r.t.=3.17 [Agilent LC1200 with SQD; XBridge C18, 2.5 μm, 4.6×50mm column; gradient of 95:5 H₂O (5 mM ammonium bicarbonate):CH₃CN to2:98 H₂O (5 mM ammonium aicarbonate):CH₃CN for 6 minutes with 1.3 mL/minflow rate]. HPLC purity: 97.52% at 254 nm r.t.=4.68. [Waters HPLC;Waters XBridge C18, 3.5 μm, 4.6×100 mm column; gradient of 90:10 H₂O (10mM ammonium acetate):CH₃CN to 5:95 H₂O (10 mM ammonium acetate):CH₃CNfor 15 minutes with 1.0 mL/min flow rate].

Example 91N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

To a stirred solution of3-bromo-N-(5-cyanopyridin-2-yl)-N-isopropylpyrazolo[1,5-a]pyridine-5-carboxamideI-71 (2 g, 5.22 mmol) in acetonitrile:H₂O (9:1) (40 mL),4-(N-methylaminocarbonyl)phenylboronic acid (1.4 g, 7.8 mmol) and NaHCO₃(860 mg, 10.23 mmol) were added and the mixture was degassed with argonfor about 15 min. To this mixture were added Pd₂(dba)₃ chloroform adduct(540 mg, 0.52 mmol), X-Phos (740 mg, 1.55 mmol) under argon atmosphere.The resulting reaction mixture was maintained at 100° C. for 2.5 h thenallowed to rt and diluted with dichloromethane, filtered through celite.The filtrate was extracted with water (100 mL) and dichloromethane(2×100 mL). The crude compound was purified by column chromatographyover silica-gel (100-200 mesh) using a solvent gradient of 80% ethylacetate and pet-ether as eluant to afford 1.4 g (61%) ofN-(5-cyanopyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide91 as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.98 (s, 1H), 8.63(d, J=7.4 Hz, 1H), 8.47 (s, 2H), 8.27-8.23 (dd, J=5.8, 2.6 Hz, 1H), 7.94(d, J=8.4 Hz, 2H), 7.75 (s, 1H), 7.50-7.58 (m, 3H), 6.75-6.72 (dd,J=5.4, 1.9 Hz, 1H), 4.96-4.91 (m, 1H), 2.82 (d, J=4.4 Hz, 3H), 1.33 (d,J=6.8 Hz, 6H). ESI-LC/MS: m/z 439 (M+H); r.t.=3.61 [Shimadzu Nexera withLCMS 2020; Pheonomenex Kinetex C18, 5 μm, 100×4.6 mm column; gradient of90:10 H₂O (10 mM ammonium bicarbonate):CH₃CN to 0:100 H₂O (10 mMammonium bicarbonate):CH₃CN for 8 minutes with 0.8 mL/min flow rate].HPLC purity: 97.31% at 254 nm; r.t.=7.34 [Waters HPLC; Waters XBridgeC18 5 μm, 4.6×250 mm column; gradient of 90:10 H₂O (10 mM ammoniumacetate):CH₃CN to 10:90 H₂O (10 mM ammonium acetate):CH₃CN for 20minutes with 1.0 mL/min flow rate].

Example 925-(5-(1-(4-cyanophenyl)-2-methylhydrazinecarbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylpicolinamide

A mixture of tert-butyl2-(3-bromopyrazolo[1,5-a]pyridine-5-carbonyl)-2-(4-cyanophenyl)-1-methylhydrazinecarboxylate(500 mg, 1.06 mmol),N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(558 mg, 2.13 mmol) and K₂CO₃ (323 mg, 2.34 mmol) in dioxane:water (3:1)(10 mL) was degassed with argon for about 10 min. To the resultingsolution were added PdCl₂(dppf).CH₂Cl₂ (174 mg, 0.213 mmol) and thereaction mixture was maintained at 90° C. for 16 h. The reaction mixturewas filtered through celite and the celite pad was washed with ethylacetate (50 mL). The filtrate was concentrated and the residue waspurified by column chromatography over silica (100-200 mesh) using asolvent gradient of 1% methanol in chloroform as eluant to afford 200 mg(36%) of tert-butyl2-(4-cyanophenyl)-1-methyl-2-(3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carbonyl)hydrazinecarboxylate92a as an yellow color solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.90 (s, 1H),8.84-8.86 (m, 1H), 8.71-8.73 (m, 1H), 8.69 (s, 1H), 8.18 (m, 2H),8.08-8.11 (m, 1H), 7.92 (d, J=6.9 Hz, 2H), 7.47-7.56 (m, 2H), 6.94-7.06(m, 1H), 3.14 (s, 3H), 2.85 (d, J=4.8 Hz, 3H), 1.32 (s, 9H); ESI-LC/MSm/z 526.03 (M+H); r.t.=2.81 [Waters Acquity UPLC with QuattroMicro;Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 98:2 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 0:100 H₂O (0.025% TFA):CH₃CN (0.025%TFA) for 5 minutes with 0.4 mL/min flow rate].

4.0 M HCl in dioxane (3.0 mL) was added to tert-butyl2-(4-cyanophenyl)-1-methyl-2-(3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carbonyl)hydrazinecarboxylate(3)_(150 mg, 0.28 mmol) and the resulting reaction mixture was stirredfor 6 h at rt. The reaction mixture was partitioned between water (20mL) and ethyl acetate (2×20 mL). The ethyl acetate layer was washed withwater, brine and dried over anhyd. Na₂SO₄ and concentrated in vacuo. Thecrude compound was purified by Preparative Thin-Layer Chromatography(Prep TLC) using 4% of methanol in dichloromethane to afford 80 mg (66%)of 5-(5-(1-(4-cyanophenyl)-2-methylhydrazinecarbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylpicolinamide 92 as a yellow solid.¹H NMR (300 MHz, DMSO-d₆): δ 8.94 (d, J=2.0 Hz, 1H), 8.80 (d, J=7.6 Hz,1H), 8.71 (m, 1H), 8.65 (s, 1H), 8.20-8.25 (m, 2H), 8.09 (d, J=8.1 Hz,1H), 7.91 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.9 Hz, 2H), 7.07-7.09 (m, 1H),6.17 (q, J=5.6, 5.3 Hz, 1H), 2.85 (d, J=5.8 Hz, 3H), 2.50 (d, J=3.6 Hz,3H); ESI-LC/MS m/z 424.3 (M−H); r.t.=3.29 [Agilent 1200 HPLC; XBridgeC18, 3.5 μm, 4.6×75 mm column; gradient of 80:20 H₂O (5 mM ammoniumbicarbonate):CH₃CN to 20:80 H₂O (5 mM ammonium bicarbonate):CH₃CN for 7minutes with 1.0 mL/min flow rate]. HPLC purity: 98.94% at 254 nm;r.t.=2.74 [Waters Acquity UPLC; Waters Acquity BEH C18, 1.7 μm, 2.1×100mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to10:90 H₂O (0.05% TFA):CH₃CN (0.05% TFA) for 6 minutes with 0.3 mL/minflow rate].

Example 93N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 2-bromo-5-cyanopyridine (5.0 g, 27.32 mmol) andcyclopropylamine (40 mL) in a sealed tube was stirred at 80° C. for 16h. The reaction mixture was partitioned between water (100 mL) and ethylacetate (150 mL). The separated organic layer was washed with brine (50ml), dried over anhydrous Na₂SO₄ and concentrated. The crude compoundwas purified by column chromatography over silica-gel (100-200 mesh)using a solvent gradient of 5% ethyl acetate in pet-ether and then 5%ethyl acetate in chloroform as eluant to afford 3.5 g (81%) of6-(cyclopropylamino)nicotinonitrile 93-1 as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 8.40 (d, J=1.8 Hz, 1H), 7.76-7.81 (m, 2H), 6.63(br.s, 1H), 2.55-2.69 (m, 1H), 0.72-0.76 (m, 2H), 0.44-0.48 (m, 2H).

Step 2

Compound 93-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield41%. Off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (d, J=1.7 Hz,1H), 8.70 (d, J=7.0 Hz, 1H), 8.33 (dd, J=2.2, 8.3 Hz, 1H), 8.23 (s, 1H),7.78 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 6.96 (d, J=7.0 Hz, 1H), 3.23-3.27(m, 1H), 0.89-0.91 (m, 2H), 0.60-0.65 (m, 2H). ESI-LC/MS: m/z 381.95(M+H) & 383.95 [(M+2)+H]; R_(t)=2.72 min [Waters Acquity UPLC withQuattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column;gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 minto 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2min with flow rate of 0.4 mL/min].

Step 3

Compound 93 was prepared using the general procedure described in SuzukiProcedure G with the appropriate starting materials. Yield 41%. Yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (d, J=1.7 Hz, 1H), 8.73 (d,J=7.5 Hz, 1H), 8.52 (s, 1H), 8.44-8.50 (m, 1H), 8.36 (dd, J=2.6, 8.7 Hz,1H), 8.03 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.8 Hz, 1H), 7.66(d, J=8.4 Hz, 2H), 7.00 (dd, J=1.8, 7.1 Hz, 1H), 3.26-3.30 (m, 1H), 2.81(d, J=4.4 Hz, 3H), 0.87-0.92 (m, 2H), 0.63-0.67 (m, 2H). ESI-LC/MS: m/z437.14 (M+H); R_(t)=2.28 min [Waters Acquity UPLC with Quattro microTQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2 min with flowrate of 0.4 mL/min]. HPLC purity=>99% at 254 nm; R_(t)=2.15 min [WatersAcquity UPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm, 2.1×100mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 minwith flow rate of 0.3 mL/min].

Example 945-Cyano-N-methyl-N-(3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide

Step 1

To a stirred solution of 4-bromopyridine (64.0 g, 40.5 mmol) in DMF (200mL) at 0° C. was added O-(mesitylsulfonyl)hydroxylamine (80.0 g, 37.1mmol) portion wise over a period of 20 min. The resultant reactionmixture was allowed to warm to room temperature and maintained at 40° C.for 16 h. The reaction mixture was cooled to 0° C., diluted with DMF(200 mL), K₂CO₃ (128 g, 92.7 mmol) followed by ethyl propiolate (43.07mL, 42.5 mmol) were added and the resulting reaction mixture was stirredat rt for 6 h. The reaction mixture was poured on to ice-cold water,extracted with ethyl acetate (2×1000 mL). The ethyl acetate layer waswashed with water, brine, dried over anhyd. Na₂SO₄ and concentrated. Thecrude compound was purified by column chromatography over silica gel(100-200 mesh) using a solvent gradient mixture of 7% ethyl acetate inpet-ether to afford 3.5 g (3%) of ethyl5-bromopyrazolo[1,5-a]pyridine-3-carboxylate 94-1 as a light brownsolid. ESI-LC/MS: m/z 269.2 (M+H) & 271.2 [(M+2)+H]; R_(t)=3.46 min[Agilent LC with Ion trap Detector; Symmetry C18, 3.5 μm, 4.6×75 mmcolumn; gradient of 50:50 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) to 10:90H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 4.0 min and hold for 3.0 min withflow rate of 1.0 mL/min].

Step 2

A suspension of ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate 94-1(1.6 g, 5.94 mmol) in 70% aq. H₂SO₄ (15 mL) was maintained at 110° C.for 16 h. The reaction mixture was cooled to room temperature and pouredinto ice-cold water. The pH was adjusted to 7.0 using aq. 1N NaOHsolution, filtered the precipitated solid, washed with water, pet-etherand dried under vacuum to afford 700 mg (60%) of5-bromopyrazolo[1,5-a]pyridine 94-2 as an off white solid. ESI-LC/MS:m/z 196.74 (M+H) & 198.71 & [(M+2)+H]; R_(t)=2.39 min [Waters AcquityUPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) holdfor 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.5 minand hold for 1.5 min with flow rate of 0.4 mL/min].

Step 3

A solution mixture of 5-bromopyrazolo[1,5-a]pyridine 94-2 (500 mg, 2.537mmol) and t-BuONa (367 mg, 3.822 mmol) in toluene (10 mL) was degassedwith argon for about 10 min. To this mixture were added Pd₂(dba)₃ (46.7mg, 0.051 mmol), BINAP (63.4 mg, 0.102 mmol) and 2.0 M methylamine inTHF (2 mL, 4.081 mmol) under argon atmosphere. The resulting reactionmixture was maintained at 100° C. for 4 h under microwave irradiation.The reaction mixture was diluted with water (30 mL) and extracted withethyl acetate (2×50 mL). The combined organic layer was washed withwater (20 mL), brine (20 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was passed through a column silica-gel(100-200 mesh) using a solvent gradient of 25% ethyl acetate inpet-ether to afford 110 mg (crude) ofN-methylpyrazolo[1,5-a]pyridin-5-amine 94-3 as an off white solid. Thecrude product was used as such for next step without furtherpurification. ESI-LC/MS: m/z 147.48 (M+H); R_(t•)=1.53 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA)in 3.5 min and hold for 1.5 min with flow rate of 0.4 mL/min].

Step 4

Compound 94-4 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield13% (over two steps). Off-white solid. ESI-LC/MS: m/z 278.3 (M+H);R_(t)=2.88 min [Agilent LC with Ion trap Detector; Symmetry C18, 3.5 μm,4.6×75 mm column; gradient of 80:20 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH)to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 4.0 min and hold for 3.0min with flow rate of 1.0 mL/min].

Step 5

To a stirred solution of5-cyano-N-methyl-N-(pyrazolo[1,5-a]pyridin-5-yl)picolinamide 94-4 (70mg, 0.252 mmol) in aceotnitrile (6 mL) was added NBS (49.4 mg, 0.277mmol) at room temperature and stirred for 16 h. Ethyl acetate (30 mL)was added to reaction mixture, washed with water (20 mL), brine (20 ml),dried over anhyd. Na₂SO₄ and concentrated to afford 90 mg (crude) ofN-(3-bromopyrazolo[1,5-a]pyridin-5-yl)-5-cyano-N-methylpicolinamide 94-5as a brown solid. The crude product was used as such for next stepwithout further purification. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.82 (s, 1H),8.64 (d, J=7.6 Hz, 1H), 8.41 (dd, J=1.2, 8.4 Hz, 1H), 8.13 (s, 1H), 7.91(d, J=8.4 Hz, 1H), 7.36 (s, 1H), 6.68-6.88 (m, 1H), 3.46 (s, 3H).ESI-LC/MS: m/z 356.26 (M+H)+ & 358.24 [(M+2)+H] R_(t)=2.32 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA)in 3.5 min and hold for 1.5 min with flow rate of 0.4 mL/min].

Step 6

Compound 94 was prepared using the general procedure described in SuzukiProcedure G with the appropriate starting materials. Yield 29% (over twosteps). Light yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H),8.69 (d, J=7.5 Hz, 1H), 8.40-8.46 (m, 3H), 7.87-7.94 (m, 3H), 7.74 (s,1H), 7.55-7.60 (m, 2H), 6.94 (s, 1H), 3.48 (s, 3H), 2.80 (d, J=4.3 Hz,3H). ESI-LC/MS: m/z 411.42 (M+H); R_(t)=1.97 min [Waters Acquity UPLCwith Quattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.5 min andhold for 1.5 min with flow rate of 0.4 mL/min]. HPLC purity=91.9% at 227nm; R_(t)=1.64 min [Waters Acquity UPLC with PDA; Waters Acquity UPLCBEH C18, 1.7 μm, 2.1×100 mm column; gradient of 70:30 H₂O (0.025%TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in4.0 min and hold for 2.0 min with flow rate of 0.3 mL/min].

Example 95N-ethyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution of 2-bromo-5-fluoropyridine (3.0 g, 17.04 mmol) and t-BuONa(2.4 g, 25.00 mmol) in toluene (60 mL) was degassed with argon for about10 min. Pd₂(dba)₃ (155 mg, 0.169 mmol), BINAP (318 mg, 0.510 mmol) andethylamine (2M in THF) (30 mL) were added under argon atmosphere. Theresulting reaction mixture was maintained at 90° C. for 1 h in sealedtube. The reaction mixture was partitioned between water (50 mL) andethyl acetate (100 mL). The organic layer was washed with water, brinesolution, dried over anhydrous Na₂SO₄ and concentrated. The crudeproduct was purified by column chromatography over silica-gel (100-200mesh) using a solvent gradient mixture of 5% ethyl acetate in pet-etherto afford 1.5 g (63%) of N-ethyl-5-fluoropyridin-2-amine 95-1 as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.90 (d, J=3.2 Hz, 1H),7.31 (td, J=2.8, 8.4 Hz, 1H), 6.44 (dd, J=3.6, 9.2 Hz, 1H), 6.39 (br.s,1H), 3.19 (q, J=7.2 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H). ESI-LC/MS: m/z141.4 (M+H); R_(t)=3.10 min [Agilent LC with Ion trap Detector;XBridge-C18, 3.5 μm, 4.6×75 mm column; gradient of 80:20 H₂O (0.005 Mammonium bicarbonate):CH₃CN to 10:90 H₂O (0.01 M ammoniumbicarbonate):CH₃CN in 4.0 min and hold for 3.0 min with flow rate of 1.0mL/min].

Step 2

Compound 95-2 was prepared using the general procedure described inAmide Coupling Method 1 with the appropriate starting materials. Yield83%. Pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.62 (d, J=10.0 Hz,1H), 8.42 (d, J=4.0 Hz, 1H), 8.19 (s, 1H), 7.71 (td, J=4.0, 11.6 Hz,1H), 7.39-7.42 (m, 2H), 6.71 (dd, J=2.8, 10.0 Hz, 1H), 3.99 (q, J=9.6Hz, 2H), 1.16 (t, J=9.6 Hz, 3H). ESI-LC/MS: m/z 369.92 (M+H) & 364.92[(M+2)+H]; R_(t)=2.75 min [Waters Acquity UPLC with SQD; Waters AcquityUPLC BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 98:02 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.8 min and to 45:55 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 2.0 min and hold for 1.0 min and to 0:100 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 0.5 minute and hold for 1.5 min withflow rate of 0.4 mL/min].

Step 3

Compound 95 was prepared using the general procedure described in SuzukiProcedure I with the appropriate starting materials. Yield 52%. Paleyellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.64 (d, J=7.4 Hz, 1H),8.45-8.48 (m, 3H), 7.92 (d, J=8.3 Hz, 2H), 7.71-7.77 (m, 2H), 7.56 (d,J=8.3 Hz, 2H), 7.42 (dd, J=4.0 Hz, 8.9 Hz, 1H), 6.76 (d, J=1.4, 7.3 Hz,1H), 4.01 (q, J=7.4 Hz, 2H), 2.82 (d, J=4.4 Hz, 3H), 1.17 (t, J=7.3 Hz,3H). ESI-LC/MS: m/z 418.1 (M+H); R_(t)=3.22 min [Agilent LC with Iontrap Detector; XBridge-C18, 3.5 μm, 4.6×75 mm column; gradient of 80:20H₂O (0.005 M ammonium bicarbonate):CH₃CN to 20:80 H₂O (0.01 M ammoniumbicarbonate):CH₃CN in 4.0 min and hold for 3.0 min with flow rate of 1.0mL/min]. HPLC purity: 98.9% at 254 nm; R_(t)=2.75 min [Waters AcquityUPLC with PDA; Waters Acquity UPLC BEH C18, 1.7 μm, 2.1×100 mm column;gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0 min withflow rate of 0.3 mL/min].

Example 96N-ethyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 2-bromo-5-trifluoromethylpyridine (3.0 g, 13.274mmol), 2.0 M ethylamine in THF (10 mL) and K₂CO₃ (3.6 g, 26.05 mmol)were stirred in sealed tube at 100° C. for 16 h. The reaction mixturewas partitioned between water (100 mL) and ethyl acetate (200 mL). Theethyl acetate layer was washed with brine (100 mL), dried over anhydrousNa₂SO₄ and concentrated to afford 1.6 g (63%) ofN-ethyl-5-(trifluoromethyl)pyridin-2-amine 1 as an off-white solid.¹H-NMR (400 MHz, DMSO-d₆): 8.37 (d, J=2.1 Hz, 1H), 7.57-7.66 (m, 2H),6.51 (d, J=8.4 Hz, 1H), 3.26-3.30 (m, 2H), 1.13 (t, J=6.9 Hz, 3H).

Step 2

Compound 96-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield64%. Off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.78 (s, 1H), 8.66(d, J=7.6 Hz, 1H), 8.22 (s, 1H), 8.15 (dd, J=2.4, 8.8 Hz, 1H), 7.49-7.53(m, 2H), 6.77 (dd, J=1.2, 7.2 Hz, 1H), 4.10 (q, J=6.8, 7.2 Hz, 2H), 1.20(t, J=6.8 Hz, 3H). ESI-LC/MS: m/z 412.95 (M+H) & 414.95 [(M+2)+H];R_(t)=3.34 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity UPLC BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O(0.025% TFA):CH₃CN (0.025% TFA) hold for 0.8 min and to 20:80 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 3.5 min and hold for 1.5 min withflow rate of 0.4 mL/min].

Step 2

Compound 96 was prepared using the general procedure described in SuzukiProcedure I with the appropriate starting materials. Yield 60%. yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.89-8.82 (m, 1H), 8.70 (dd, J=0.69,7.22 Hz, 1H), 8.50 (s, 1H), 8.40-8.48 (m, 1H), 8.19 (dd, J=2.32, 8.60Hz, 1H), 7.91 (d, J=8.28 Hz, 2H), 7.84 (d, J=0.72 Hz, 1H), 7.51-7.59 (m,3H), 6.83 (dd, J=1.82, 7.22 Hz, 1H), 4.13 (q, J=7.03 Hz, 2H), 2.82 (d,J=4.52 Hz, 3H), 1.22 (t, J=7.09 Hz, 3H). ESI-LC/MS: m/z 467.5 (M+H);R_(t)=0.95 min [Agilent UHPLC 1290 coupled with API 3200; Acquity UPLCBEH C18 column, 1.7 μm, 2.1×50 mm; gradient of 98:2 H₂O (0.1%HCOOH):CH₃CN to 2:98 H₂O (0.1% HCOOH):CH₃CN for 2 min run time with 1.0mL/min flow rate]. HPLC purity=>99% at 254 nm; R_(t)=1.64 min [WatersAcquity UPLC equipped with a Acquity UPLC HSS T3 column, 1.8 μm, 2.1×50mm; gradient of 95:5 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1%HCOOH):CH₃CN for 2 min run time with 1.0 mL/min flow rate].

Example 97N-(4-Cyanophenyl)-N-methyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound I-8 was prepared using the general procedure described in AmideCoupling-Method 1 with the appropriate starting materials. Yield 51%.White solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.63 (d, J=7.0 Hz, 1H), 8.20(s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.50-7.52 (m, 3H), 6.78 (dd, J=1.7, 7.4Hz, 1H), 3.44 (s, 3H). ESI-LC/MS: m/z 355.05 (M+H) & 357.03 [(M+2)+H];R_(t)=2.64 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min].

Step 2

Compound 97 was prepared using the general procedure described in SuzukiProcedure G with the appropriate starting materials. Yield 13%. Yellowsolid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.82 (d, J=1.3 Hz, 1H), 8.69-8.74(m, 2H), 8.63 (s, 1H), 8.06-8.10 (m, 2H), 7.96 (s, 1H), 7.83 (d, J=8.8Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 6.85 (dd, J=1.8, 7.5 Hz, 1H), 3.46 (s,3H), 2.86 (d, J=4.9 Hz, 3H). ESI-LC/MS: m/z 411.20 (M+H); R_(t)=2.41 min[Waters Acquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in2.5 min and hold for 2 min with flow rate of 0.4 mL/min]. HPLC purity:98.3% at 254 nm; R_(t)=3.05 min [Waters Acquity UPLC with PDA detector;Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 90:10 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4 min and hold for 2 min with flow rate of 0.3 mL/min].

Example 983-(5-Amino-6-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

5-Bromo-2-chloropyridin-3-amine (500 mg, 2.410 mmol),bis(pinacolato)diboron (672.9 mg, 2.649 mmol) and potassium acetate (467mg, 4.765 mmol) in 1,4-dioxane (15 mL) were degassed with argon gas for15 min. PdCl₂(dppf)dichloromethane complex (98 mg, 0.120 mmol) was addedand the reaction mixture was stirred at 100° C. for 4 h. The reactionmixture was diluted with ethyl acetate, filtered through celite and thefiltrate was concentrated to afford 800 mg (crude) of2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine98-1 as a deep brown solid. The crude product was used as such for thenext step without further purification. ESI-LC/MS: m/z 254.9 (M+H) &256.9 [(M+H)+2]; R_(t)=3.14 min [Agilent LC with Ion trap Detector;Xterra MS-C18, 2.5 μm, 4.6×50 mm column; gradient of 80:20 H₂O (0.01 Mammonium bicarbonate):CH₃CN to 10:90 H₂O (0.01 M ammoniumbicarbonate):CH₃CN in 4.0 min and hold for 3.0 min with flow rate of 1.0mL/min].

Step 2

A solution mixture of3-bromo-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide1 (150 mg, 0.42 mmol),2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine98-1 (106.9 mg, crude) and 1N Na₂CO₃ solution (0.42 mL, 0.84 mmol) in1,4-dioxane (15 mL) was degassed with argon gas for 10 min.PdCl₂(dppf)dichloromethane complex (34.4 mg, 0.042 mmol) was added andstirred at 100° C. for 3 h in sealed tube. The reaction mixture wascooled to room temperature and partitioned between water and ethylacetate. The organic layer was washed with water, brine, dried overanhydrous Na₂SO₄ solution and concentrated under reduced pressure. Thecrude compound was purified by column chromatography over silica gel(100-200 mesh) using a solvent gradient of 2% methanol in chloroform asan eluant to afford 25 mg (20% over two steps) of3-(5-amino-6-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide98 as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.82 (d, J=2.2 Hz,1H), 8.69 (d, J=7.5 Hz, 1H), 8.44 (s, 1H), 8.24 (dd, J=2.2, 8.7 Hz, 1H),8.02 (s, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.41 (d,J=1.8 Hz, 1H), 6.78 (dd, J=2.8, 7.5 Hz, 1H), 5.67 (s, 2H), 3.53 (s, 3H).ESI-LC/MS: m/z 404.09 (M+H) & 406.04 [(M+2)H+]; R_(t)=1.65 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 85:15 H₂O (0.025% TFA):CH₃CN (0.025%TFA) to 5:95 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for1.0 min with flow rate of 0.4 mL/min]. HPLC purity: 97.1% at 254 nm;R_(t)=2.452 min [Waters Acquity UPLC with PDA; Waters Acquity BEH C18,1.7 μm, 2.1×100 mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN(0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min andhold for 2.0 min with flow rate of 0.3 mL/min].

Example 99N-(4-Chlorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound 99-1 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield50%. White solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.62 (d, J=7.0 Hz, 1H),8.19 (s, 1H), 7.48 (s, 1H), 7.33-7.39 (m, 4H), 6.77 (d, J=6.6 Hz, 1H),3.35 (s, 3H). ESI-LC/MS: m/z 363.94 (M+H) & 365.92 [(M+2)+H]; R_(t)=3.01min [Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 3.0 min and hold for 2.0 min with flow rate of 0.4mL/min].

Step 2

Compound 99 was prepared using the general procedure described in SuzukiProcedure H with the appropriate starting materials. Yield 32%). Lightyellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.66 (d, J=7.0 Hz, 1H),8.45-8.52 (m, 2H), 7.91 (d, J=8.30 Hz, 2H), 7.79 (s, 1H), 7.52 (d,J=8.30 Hz, 2H), 7.36-7.46 (m, 4H), 6.85 (d, J=7.0 Hz, 1H), 3.41 (s, 3H),2.81 (d, J=4.40 Hz, 3H). ESI-LC/MS: m/z 419.13 (M+H) & 421.11 [(M+2)+H];R_(t)=2.52 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min]. HPLC purity: 98.6% at 278 nm; R_(t)=3.42 min [WatersAcquity UPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0 min withflow rate of 0.3 mL/min].

Example 1003-(4-Carbamoylphenyl)-N-(4-chlorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Compound 100 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 15%.Light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.66 (d, J=7.0 Hz, 1H),8.47 (s, 1H), 8.04 (s, 1H), 7.95 (d, J=8.30 Hz, 2H), 7.78 (s, 1H), 7.51(d, J=8.40 Hz, 2H), 7.38-7.47 (m, 5H), 6.85-6.87 (m, 1H), 3.41 (s, 3H).ESI-LC/MS: m/z 405.12 (M+H) & 407.04 [(M+2)H+]; R_(t)=2.41 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA)in 3.0 min and hold for 2.0 min with flow rate of 0.4 mL/min]. HPLCpurity: 99.4% at 254 nm; R_(t)=3.25 min [Waters Acquity UPLC with PDA;Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 90:10 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4.0 min and hold for 2.0 min with flow rate of 0.3 mL/min].

Example 1014-(5-((5-Cyanopyridin-2-yl)(methyl)carbamoyl)pyrazolo[1,5-a]pyridin-3-yl)benzoicacid

Compound 101 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 72%.Yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.87 (d, J=2.4 Hz, 1H), 8.72(d, J=7.2 Hz, 1H), 8.51 (s, 1H), 8.27 (dd, J=2.2, 8.4 Hz, 1H), 7.95-8.02(m, 3H), 7.57-7.66 (m, 3H), 6.85 (d, J=8.8 Hz, 1H), 3.53 (s, 3H).ESI-LC/MS: m/z 398.15 (M+H) & 399.05 [(M+2)+H]; R_(t)=2.36 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA)in 3.0 min and hold for 2.0 min with flow rate of 0.4 mL/min. HPLCPurity: >99% at 297 nm; R_(t)=2.30 min. Waters Acquity UPLC with PDA;Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 90:10 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4.0 min and hold for 2.0 min with flow rate of 0.3 mL/min].

Example 102N-(5-Cyanopyridin-2-yl)-3-(4-((2-hydroxyethyl)carbamoyl)phenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

To a solution mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.0 g, 4.03mmol), HOBT (925.3 mg, 6.85 mmol) and EDC.HCl (1.15 g, 5.98 mmol) indichloromethane (20 mL) was stirred at room temperature for 5 min andwere added ethanolamine (270.5 mg, 4.42 mmol) and TEA (1.15 mL, 8.19mmol). The resulting reaction mixture was stirred at temperature for 16h. The reaction mixture was partitioned between water and ethyl acetate.The organic layer was washed with water, brine, dried over anhydrousNa₂SO₄ and the solvent was distilled off under reduced pressure toafford 1.0 g (crude) of (4-((2-hydroxyethyl)carbamoyl)phenyl)boronicacid 102-1 as an off white solid. The crude product was used as such forthe next step without further purification. ESI-LC/MS: m/z 209.95 (M+H);R_(t)=0.72 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min].

Step 2

The compound 102 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 10%(over two steps). Light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.86(s, 1H), 8.71 (d, J=7.0 Hz, 1H), 8.54 (s, 1H), 8.47-8.52 (m, 1H), 8.27(dd, J=2.2, 8.8 Hz, 1H), 8.06 (s, 1H), 7.93 (d, J=5.7 Hz, 1H), 7.61-7.66(m, 3H), 6.84 (d, J=7.0 Hz, 1H), 4.77 (t, J=5.7 Hz, 1H), 3.50-3.53 (s,5H), 3.37-3.39 (m, 2H). ESI-LC/MS: m/z 441.19 (M+H); R_(t)=2.09 min[Waters Waters Acquity UPLC with Quattro-micro detector; Waters AcquityBEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min]. HPLC Purity: 98.1% at 254 nm; R_(t)=1.63 min [WatersAcquity UPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0 min withflow rate of 0.3 mL/min].

Example 103N-Methyl-3-(4-(methylcarbamoyl)phenyl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound 103-1 was prepared using the general procedure described inAmide Coupling Method 1 with the appropriate starting materials. Yield27%. Off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.64 (d, J=7.1 Hz,1H), 8.19 (s, 1H), 7.68-7.70 (m, 2H), 7.49-7.54 (m, 3H), 6.80 (dd,J=1.7, 7.0 Hz, 1H), 3.45 (s, 3H). ESI-LC/MS: m/z 397.96 (M+H) & 400.01[(M+2)+H]; R_(t)=2.77 min [Waters Acquity UPLC with Quattro-microdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min withflow rate of 0.4 mL/min].

Step 2

Compound 103 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 22%.Light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.68 (d, J=7.0 Hz, 1H),8.44-8.52 (m, 2H), 7.89 (d, J=8.30 Hz, 2H), 7.79 (s, 1H), 7.74 (d, J=8.7Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 6.88 (dd,J=1.3, 7.0 Hz, 1H), 3.47 (s, 3H), 2.81 (d, J=4.4 Hz, 3H). ESI-LC/MS: m/z453.16 (M+H); R_(t)=2.60 min [Waters Acquity UPLC with Quattro-microdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min withflow rate of 0.4 mL/min]. HPLC purity: 98.7% at 281 nm; R_(t)=2.74 min[Waters Acquity UPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0min with flow rate of 0.3 mL/min].

Example 1043-(4-((2-Aminoethyl)carbamoyl)phenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

To a solution mixture of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.0 g, 4.03mmol), HOBT (925.3 mg, 6.85 mmol) and EDC.HCl (1.15 g, 5.98 mmol) indichloromethane (20 mL) was stirred at room temperature for 5 min andwere added tert-butyl(2-aminoethyl)carbamate (645 mg, 4.03 mmol) and TEA(1.15 mL, 8.19 mmol). The resulting reaction mixture was stirred attemperature for 16 h. The reaction mixture was partitioned between waterand ethyl acetate. The organic layer was washed with water, brine, driedover anhydrous Na₂SO₄ and the solvent was distilled off under reducedpressure to afford 1.0 g (crude) oftert-Butyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)ethyl)carbamate 104-1 as white solid. The crude product was used as such forthe next step without further purification.

Step 2

The compound 104-2 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. The yellowcolor gum crude product was used as such for the next step withoutfurther purification. ESI-LC/MS: m/z 540.13 (M+H); R_(t)=2.67 min[Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 3.0 min and hold for 2.0 min with flow rate of 0.4mL/min].

Step 3

A solution mixture of tert-butyl2-(4-(5-((5-cyanopyridin-2-yl)(methyl)carbamoyl)pyrazolo[1,5-a]pyridin-3-yl)benzamido)ethylcarbamate104-2 (400 mg, crude) in dioxane.HCl (4 mL) was stirred at roomtemperature for 16 h. The volatiles were distilled off under reducedpressure. The crude compound was purified by prep-TLC to afford 19 mg(4% over three steps) of3-(4-(2-aminoethyl)carbamoyl)phenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide104 as light yellow solid. ¹H-NMR (400 MHz, DMSO-d₆, D₂O Exchange): δ8.53-8.85 (m, 3H), 8.22 (d, J=7.0 Hz, 1H), 7.84-8.00 (m, 3H), 7.39-7.77(m, 3H), 6.88 (d, J=6.6 Hz, 1H), 3.54-3.59 (m, 5H), 3.02 (s, 2H).ESI-LC/MS: m/z 440.17 (M+H); R_(t)=1.85 min [Waters Acquity UPLC withQuattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min andhold for 2.0 min with flow rate of 0.4 mL/min]. HPLC purity: 94.9% at294 nm; R_(t)=2.36 min [Waters Acquity UPLC with PDA; Waters Acquity BEHC18, 1.7 μm, 2.1×100 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min andhold for 2.0 min with flow rate of 0.3 mL/min].

Example 1053-(4-Carbamoylphenyl)-N-(4-cyanophenyl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 105 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 14%.Light green solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.89 (d, J=7.50 Hz, 1H),8.60 (s, 1H), 8.50 (s, 1H), 7.98-8.06 (m, 3H), 7.80 (d, J=8.30 Hz, 2H),7.42 (d, J=8.8 Hz, 2H), 7.39 (dd, J=1.8, 7.5 Hz, 2H), 6.98 (t, J=5.7 Hz,1H), 6.74 (d, J=8.70 Hz, 2H), 4.46 (t, J=5.7 Hz, 2H), 3.55-3.60 (m, 2H).ESI-LC/MS: m/z 426.16 (M+H); R_(t)=2.51 min [Waters Acquity UPLC withQuattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column;gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 minto 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2min with flow rate of 0.4 mL/min]. HPLC purity: 97.0% at 285 nm;R_(t)=2.542 min [Waters Acquity UPLC with PDA detector; Waters AcquityBEH C18, 1.7 μm, 2.1×100 mm column; gradient of 70:30 H₂O (0.025%TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in4 min and hold for 2 min with flow rate of 0.3 mL/min].

Example 106N-(5-Cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound 106-1 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Thepale brown solid crude product (900 mg) was used as such for the nextstep without further purification. ESI-LC/MS: m/z 343.41 [(M+2)H+];R_(t)=2.60 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min].

Step 2

Compound 106 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 9%(over two steps). Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.81 (s,1H), 8.91 (s, 1H), 8.86 (d, J=7.0 Hz, 1H), 8.73 (s, 1H), 8.59 (s, 1H),8.46-8.52 (m, 1H), 8.33-8.40 (m, 2H), 7.93-7.99 (m, 4H), 7.41 (d, J=7.0Hz, 1H), 2.81 (d, J=4.4 Hz, 3H). ESI-LC/MS: m/z 397.13 (M+H); R_(t)=2.39min [Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 3.0 min and hold for 2.0 min with flow rate of 0.4mL/min]. HPLC purity: 98.3% at 294 nm; R_(t)=2.28 min [Waters HPLC withPDA; Xterra RP18, 5.0 μm, 4.6×150 mm column; gradient of 70:30 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4.0 min and hold for 2.0 min with flow rate of 0.3 mL/min.

Example 1073-(6-Chloro-5-(methylsulfonamido)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide(NVP-LMX045)

To a stirred solution of3-(5-amino-6-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide 98 (50 mg, 0.123 mmol) indichloromethane was added pyridine (0.019 mL, 0.236 mmol),methanesulfonyl chloride (0.01 mL, 0.129 mmol) and maintained at roomtemperature for 48 h. The reaction mixture was partitioned between waterand dichloromethane. The organic layer was washed with water, brine,dried over anhydrous Na₂SO₄ solution and concentrated under reducedpressure. The crude compound was purified by prep-TLC to afford 7 mg(12%) of3-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide107 as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): 9.87 (s, 1H),8.80 (d, J=1.70 Hz, 1H), 8.75 (d, J=7.10 Hz, 1H), 8.60 (s, 1H), 8.52 (s,1H), 8.23 (dd, J=2.2, 8.8 Hz, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.62 (d,J=8.8 Hz, 1H), 6.86 (dd, J=1.8, 7.0 Hz, 1H), 3.53 (s, 3H), 3.16 (s, 3H).ESI-LC/MS: m/z 482.13 (M+H) & 483.99 [(M+2)+H]; R_(t)=2.30 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA)in 3.0 min and hold for 2.0 min with flow rate of 0.4 mL/min]. HPLCpurity: 96.1% at 254 nm; R_(t)=2.19 min [Waters Acquity UPLC with PDA;Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 70:30 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4.0 min and hold for 2.0 min with flow rate of 0.3 mL/min].

Example 1083-(2-Aminopyridin-4-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 4-bromopyridin-2-amine (1.0 g, 5.78 mmol),bis(pinacolato)diboron (1.6 g, 6.299 mmol) and potassium acetate (1.12g, 11.42 mmol) in 1,4-dioxane (15 mL) was degassed with argon gas for 15min. Pd₂(dba)₃ (265.9 mg, 0.290 mmol) and X-phos (277 mg, 0.580 mmol)were added. The resulting reaction mixture was stirred at 110° C. for 4h, cooled to room temperature and filtered through celite. The filtratewas concentrated under reduced pressure to obtain 500 mg of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 108-1 asa brown color solid. The crude product was used as such in next stepwithout further purification

Step 2

To a stirred solution of3-bromo-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamideI-9 (300 mg, 0.84 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 108-1(223 mg, crude), K₃PO₄ (1.12 g, 5.28 mmol) in dioxane/water (9:1) (10mL) was degassed with argon for about 10 min. Pd₂(dba)₃ (38.65 mg, 0.042mmol) was added under argon atmosphere. The resulting reaction mixturewas maintained at 90-100° C. for 16 h. The reaction mass was cooled toroom temperature and filtered through celite. The filtrate waspartitioned between water (10 mL) and ethyl acetate (20 mL). The organiclayer was washed water, brine, dried over anhyd. Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyover silica gel (100-200 mesh) using a solvent gradient of 1-2% methanolin chloroform to afford 120 mg (9% over two steps) of3-(2-aminopyridin-4-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide108 as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H), 8.71(d, J=7.0 Hz, 1H), 8.52 (s, 1H), 8.27 (d, J=2.2, 8.8 Hz, 1H), 8.06 (s,1H), 7.93 (d, J=5.7 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 6.74-6.82 (m, 3H),6.18 (brs, 2H), 3.53 (s, 3H). ESI-LC/MS: m/z 370.14 (M+H); R_(t)=1.97min [Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 3.0 min and hold for 2.0 min with flow rate of 0.4mL/min]. HPLC purity: 98.0% at 298 nm; R_(t)=1.93 min [Waters AcquityUPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column;gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0 min withflow rate of 0.3 mL/min].

Example 109N-(4-Chlorophenyl)-N-methyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 109 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 15%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.84 (s, 1H), 8.68-8.74 (m,2H), 8.61 (s, 1H), 8.02-8.09 (m, 2H), 7.91 (s, 1H) 7.37-7.44 (m, 4H),6.86 (d, J=7.1 Hz, 1H), 3.41 (s, 3H), 2.86 (d, J=4.4 Hz, 3H). ESI-LC/MS:m/z 420.15 (M+H) & 422.13 [(M+2)+H]; R_(t)=2.76 min [Waters Acquity UPLCwith Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 80:20 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3 min and hold for 2 min withflow rate of 0.4 mL/min]. HPLC purity: 98.4% at 254 nm; R_(t)=2.68 min[Waters Acquity UPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm,2.1×100 mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA)to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 minwith flow rate of 0.3 mL/min].

Example 110N-(4-Cyanophenyl)-N-(2-hydroxyethyl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A mixture of 4-fluorobenzonitrile (2.0 g, 16.52 mmol), 2-aminoethanol(1.21 mL, 20.16 mmol) and potassium carbonate (2.76 g, 20.00 mmol) inDMSO (16 mL) was stirred at 100° C. for 16 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate (4×200 mL). Thecombined organic layer was washed with water, brine solution, dried overNa₂SO₄ and concentrated. The crude product was passed through a columnof silica gel (100-200 mesh) using a solvent gradient of 30% ethylacetate in pet-ether as eluant and obtained 1.2 g (44%) of4-((2-hydroxyethyl)amino)benzonitrile 110-1 as a yellow solid. ¹H NMR(400 MHz, CDCl₃): δ 7.42 (d, J=8.8 Hz, 2H), 6.60 (d, J=8.8 Hz, 2H),4.55-4.65 (m, 1H), 3.85-3.90 (m, 2H), 3.33 (d, J=5.9 Hz, 2H). ESI-LC/MS:m/z 163.4 (M+H); R_(t)=2.71 min [Agilent LC with Ion trap Detector;Waters Symmetry C18, 3.5 μm, 4.6×75 mm column; gradient of 80:20 H₂O(0.1% HCOOH):CH₃CN (0.1% HCOOH) to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1%HCOOH) in 3 min and hold for 4 min with flow rate of 1.0 mL/min].

Step 2

To a solution of 4-(2-hydroxyethylamino)benzonitrile 110-1 (1.0 g, 6.17mmol) in dichloromethane (20 mL) was added TBDMS-Cl (930 mg, 6.17 mmol),TEA (1.78 mL, 12.76 mmol) and DMAP (6 mg, 0.049 mmol) and the resultingreaction mixture was stirred at rt for 16 h. The reaction mixture wasdiluted with water and extracted with dichloromethane (3×200 mL). Theorganic layer was separated and washed with water, brine solution, driedover Na₂SO₄ and concentrated. The crude product was passed through acolumn of silica gel (100-200 mesh) using a solvent gradient of 3%methanol in chloroform as eluant and obtained 900 mg (53%) of4-(2-(tert-butyldimethylsilyloxy)ethylamino)benzonitrile 110-2 as acolorless liquid. ¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, J=8.8 Hz, 2H),6.57 (d, J=8.8 Hz, 2H), 4.60-4.50 (m, 1H), 3.82 (t, J=5.3 Hz, 2H), 3.25(q, J=4.3, 10.6 Hz, 2H), 0.90 (s, 9H), 0.06 (s, 6H).

Step 3

Compound 110-3 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield64%. Off-white solid. ESI-LC/MS: m/z 499.08 (M+H) & 501.07 [(M+2)+H];R_(t)=3.92 min [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4mL/min].

Step 4

To a solution of 3 (700 mg, 1.40 mmol) in THF (20 mL) was added TBAF (2Msolution in THF) (10 mL) and stirred at rt for 1 h. The reaction mixturewas diluted with water, concentrated to remove the solvent and theresidue was extracted with ethyl acetate twice. The organic layer waswashed with water, brine, dried over anhydrous Na₂SO₄ and concentrated.The crude compound was washed with pentane to afford 270 mg (50%) of3-bromo-N-(4-cyanophenyl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyridine-5-carboxamide110-4 as an off-white solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.86 (d, J=7.5Hz, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.36 (dd,J=1.8, 7.5 Hz, 1H), 6.96-7.00 (m, 1H), 6.76 (d, J=8.8 Hz, 2H), 4.44 (t,J=5.3 Hz, 2H), 3.57 (q, J=5.3, 11.0 Hz, 2H). ESI-LC/MS: m/z 385.04 (M+H)& 387.02 [(M+2)H+]; R_(t)=3.00 min [Waters Acquity UPLC with Quattromicro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2 min with flowrate of 0.4 mL/min].

Step 5

Compound 110 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 15%.Light green solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.89 (d, J=7.5 Hz, 1H),8.50-8.61 (m, 3H), 7.97 (d, J=7.9 Hz, 2H), 7.80 (d, J=8.30 Hz, 2H), 7.43(d, J=8.30 Hz, 2H), 7.36 (d, J=7.0 Hz, 1H), 6.95-7.05 (m, 1H), 6.74 (d,J=8.30 Hz, 2H), 4.40-4.50 (m, 2H), 3.54 (d, J=4.9 Hz, 2H), 2.81 (d,J=4.0 Hz, 3H). ESI-LC/MS: m/z 440.17 (M+H); R_(t)=2.73 min [WatersAcquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm,2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA)hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 minand hold for 2 min with flow rate of 0.4 mL/min]. HPLC purity: 96.8% at284 nm; R_(t)=2.775 min [Waters Acquity UPLC with PDA detector; WatersAcquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 70:30 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4 min and hold for 2 min with flow rate of 0.3 mL/min].

Example 111N-(5-(2-Aminoethoxyl)pyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A suspension of 2-bromo-5-hydroxypyridine (250 mg g, 1.43 mmol),tert-butyl(2-bromoethyl)carbamate (321.8 g, 1.43 mmol) and potassiumcarbonate (592 mg, 4.31 mmol) in acetonitrile (5 mL) was stirred at 70°C. for 24 h. The reaction mixture was diluted with water and extractedwith ethyl acetate. The organic layer was washed with water, brine,dried over anhydrous Na₂SO₄ and concentrated. The crude compound waspurified by column chromatography over silica gel (100-200 mesh) using asolvent gradient mixture of 25% of ethyl acetate in pet-ether as eluantto afford 90 mg (20%) of tert-butyl2-(6-bromopyridin-3-yloxy)ethylcarbamate 111-1 as a pale yellow solid.¹H NMR (400 MHz, CDCl₃): δ 8.06 (d, J=3.0 Hz, 1H), 7.37 (d, J=8.8 Hz,1H), 7.10 (dd, J=3.1, 8.4 Hz, 1H), 4.95-5.05 (m, 1H), 4.04 (t, J=5.2 Hz,2H), 3.54 (d, J=5.3 Hz, 2H), 1.45 (s, 9H). ESI-LC/MS: m/z 319.2[(M+2)+H]; R_(t)=2.72 min [Agilent LC with Ion trap Detector; WatersSymmetry C18, 3.5 μm, 4.6×75 mm column; gradient of 50:50 H₂O (0.1%HCOOH):CH₃CN (0.1% HCOOH) to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH)in 3 min and hold for 4 min with flow rate of 1.0 mL/min].

Step 2

A solution mixture of tert-butyl2-(6-bromopyridin-3-yloxy)ethylcarbamate 111-1 (1.0 g, 3.16 mmol), 40%methylamine in water (10 mL) and CuSO₄.5H₂O (236 mg, 0.94 mmol) insealed tube was stirred at 70° C. for 1 h then allowed to rt andfiltered. The filtrate was concentrated to afford 700 mg (83%) oftert-butyl 2-(6-(methylamino)pyridin-3-yloxy)ethylcarbamate 111-2 as anoff-white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.82 (s, 1H), 7.12 (dd,J=2.6, 8.7 Hz, 1H), 6.36 (d, J=9.2 Hz, 1H), 4.98 (br s, 1H), 4.28 (br s,1H), 3.96 (t, J=5.3 Hz, 2H), 3.49 (d, J=4.9 Hz, 2H), 2.89 (d, J=4.9 Hz,3H), 1.45 (s, 9H). ESI-LC/MS: m/z 268.16 (M+H); R_(t)=1.76 min [WatersAcquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm,2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA)hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 minand hold for 2 min with flow rate of 0.4 mL/min].

Step 3

Compound 111-3 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Thecrude product (100 mg) was used as such for the next step withoutfurther purification. ESI-LC/MS: m/z 490.5 (M+H); R_(t)=4.08 [Agilent LCwith Ion trap Detector; Xterra MS-C18, 2.5 μm, 4.6×50 mm column;gradient of 80:20 H₂O (0.01 M ammonium bicarbonate):CH₃CN to 10:90 H₂O(0.01 M ammonium bicarbonate):CH₃CN in 4.0 min and hold for 3.0 min withflow rate of 1.0 mL/min].

Step 4

Compound 111-4 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. The crudeproduct (200 mg) was used as such for next step without furtherpurification. ESI-LC/MS: m/z 545.31 (M+H); R_(t)=2.33 min [WatersAcquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm,2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA)hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 minand hold for 2 min with flow rate of 0.4 mL/min].

Step 5

A solution mixture of tert-butyl2-(6-(N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamido)pyridin-3-yloxy)ethylcarbamate111-4 (200 mg, 0.36 mmol) in 1,4-dioxane HCl (4.0 M, 5 mL) was stirredat rt for 1 h. The reaction mixture was diluted with ice-water andbasified (pH: 8.0) with saturated NaHCO₃ solution and then extractedwith ethyl acetate. The organic layer was washed with water, brinesolution, dried over Na₂SO₄ and concentrated. The crude compound waspurified by prep-HPLC to afford 80 mg (4% over three steps) ofN-(5-(2-aminoethoxyl)pyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide111 as a yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.65 (d, J=7.0 Hz,1H), 8.42-8.52 (m, 2H), 8.15 (d, J=2.2 Hz, 1H), 7.91 (d, J=7.9 Hz, 2H),7.70 (s, 1H), 7.53 (d, J=7.9 Hz, 2H), 7.36-7.42 (m, 1H), 7.28 (d, J=8.8Hz, 1H), 6.80 (d, J=6.6 Hz, 1H), 3.90 (brs, 2H), 3.40 (s, 3H), 3.20(brs, 1H), 2.75-2.80 (m, 6H). ESI-LC/MS: m/z 445.20 (M+H); R_(t)=1.58min [Waters Acquity UPLC with Quattro micro TQD; Waters Acquity BEH C18,1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 2.5 min and hold for 2 min with flow rate of 0.4 mL/min]. HPLCpurity: 98.5% at 254 nm; R_(t)=2.11 min [Waters Acquity UPLC with PDAdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 min with flow rate of0.3 mL/min].

Example 112N-(5-Cyanopyridin-2-yl)-N-cyclobutyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 2-bromo-5-cyanopyridine (10.0 g, 54.64 mmol),cyclobutylamine (9.36 mL, 109.6 mmol) in dioxane (100 mL) was stirred at100° C. for 16 h in sealed tube. The reaction mixture was partitionedbetween water (200 mL) and ethyl acetate (100 mL). The ethyl acetatelayer was washed with brine (100 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyover silica gel (100-200 mesh) using a solvent gradient of 20% ethylacetate in pet-ether as eluant to give 7.0 g (74%) of6-(cyclobutylamino)nicotinonitrile 112-1 as an off-white solid. ¹H NMR(300 MHz, DMSO-d₆): δ 8.36 (d, J=2.1 Hz, 1H), 7.84 (d, J=6.6 Hz, 1H),7.67 (d, J=8.4 Hz, 1H), 6.47 (d, J=9.0 Hz, 1H), 4.32 (br. s, 1H),2.10-2.35 (m, 2H), 1.82-1.96 (m, 2H), 1.61-1.73 (m, 2H). ESI-LC/MS: m/z172.0 (M−H); R_(t)=4.28 min [Agilent LC with Ion trap Detector;XBridge-C18, 3.5 μm, 4.6×75 mm column; gradient of 80:20 H₂O (0.005 Mammonium bicarbonate):CH₃CN to 20:80 H₂O (0.005 M ammoniumbicarbonate):CH₃CN in 4.0 min and hold for 3.0 min with flow rate of 1.0mL/min].

Step 2

Compound 112-2 was prepared using the general procedure described inAmide Coupling—Method 1 with the appropriate starting materials. Yield33%. Yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (d, J=2.2 Hz, 1H),8.61 (d, J=7.0 Hz, 1H), 8.30 (dd, J=2.2, 7.9 Hz, 1H), 8.19 (s, 1H), 7.58(d, J=8.4 Hz, 1H), 7.39 (s, 1H), 6.72 (dd, J=1.7, 8.5 Hz, 1H), 4.85-4.90(m, 1H), 2.07-2.24 (m, 4H), 1.60-1.66 (m, 2H). ESI-LC/MS m/z 396.10(M+H) & 397.99 [(M+2)+H]; R_(t)=2.88 min [Waters Acquity UPLC withQuattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column;gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 minto 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2min with flow rate of 0.4 mL/min].

Step 3

Compound 112 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 22%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.98 (d, J=2.2 Hz, 1H), 8.64(d, J=7.40 Hz, 1H), 8.46-8.52 (m, 2H), 8.33 (dd, J=2.2, 8.4 Hz, 1H),7.94 (d, J=8.30 Hz, 2H), 7.76 (s, 1H), 7.62 (d, J=8.30 Hz, 1H), 7.56 (d,J=8.4 Hz, 2H), 6.77 (dd, J=1.8, 7.1 Hz, 1H), 4.91-4.95 (m, 1H), 2.82 (d,J=4.4 Hz, 3H), 2.20-2.26 (m, 2H), 2.07-2.15 (m, 2H), 1.59-1.69 (m, 2H).ESI-LC/MS: m/z 451.18 (M+H); R_(t)=2.42 min [Waters Acquity UPLC withQuattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column;Gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 minto 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2min with flow rate of 0.4 mL/min]. HPLC purity: 97.0% at 282 nm;R_(t)=2.293 min [Waters Acquity UPLC with PDA detector; Waters AcquityHSS T3, 1.7 μm, 2.1×100 mm column; gradient of 70:30 H₂O (0.025%TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in4 min and hold for 2 min with flow rate of 0.4 mL/min].

Example 113N-(5-Cyanopyridin-2-yl)-N-methyl-3-(4-(piperidin-4-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound 113-1 was prepared using the general procedure described inAmide Coupling-Method 2 with the appropriate starting materials. Thecolorless crude gum product was used as such for the next step withoutfurther purification. ESI-LC/MS: m/z 431.29 (M+H); R_(t)=3.27 min[Waters Waters Acquity UPLC with Quattro-micro detector; Waters AcquityBEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min].

Step 2

Compound 113-2 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. The yellowcolor crude was used as such for the next step without furtherpurification. ESI-LC/MS: m/z 580.19 (M+H); R_(t)=2.85 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA)in 3.0 min and hold for 2.0 min with flow rate of 0.4 mL/min].

Step 3

A solution mixture of tert-butyl4-(4-(5-((5-cyanopyridin-2-yl)(methyl)carbamoyl)pyrazolo[1,5-a]pyridin-3-yl)benzamido)piperidine-1-carboxylate113-2 (450 mg, crude) and 1,4-dioxane.HCl (4M) (3.0 mL) in 1,4-dioxane(10 mL) was stirred at room temperature for 1 h. Diethyl ether was addedto reaction mixture and filtered. The solid collected was dissolved inwater, basified with sat. NaHCO₃ to pH 10 and extracted with 10%methanol in chloroform. The organic extracts were dried over Na₂SO₄ andconcentrated. The crude compound was purified by prep-TLC followed byprep-HPLC gave 70 mg (13%) ofN-(5-cyanopyridin-2-A-N-methyl-3-(4-(piperidin-4-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide113 as yellow color solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.85 (d, J=1.7Hz, 1H), 8.72 (d, J=7.4 Hz, 1H), 8.53 (s, 1H), 8.35 (d, J=7.9 Hz, 1H),8.25 (dd, J=2.2, 8.3 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J=8.3 Hz, 2H),7.61-7.65 (m, 3H), 6.85 (dd, J=1.8, 7.4 Hz, 1H), 3.92-3.94 (m, 1H), 3.53(s, 3H), 3.01-3.12 (m, 2H), 2.67-2.74 (m, 2H), 1.82-1.85 (m, 2H),1.54-1.59 (m, 2H). ESI-LC/MS: m/z 480.40 (M+H); R_(t)=2.55 min [AgilentLC with Ion trap Detector; Symmetry C18, 3.5 μm, 4.6×75 mm column;gradient of 80:20 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) to 10:90 H₂O (0.1%HCOOH):CH₃CN (0.1% HCOOH) in 4.0 min and hold for 3.0 min with flow rateof 1.0 mL/min]. HPLC purity: 97.5% at 294 nm; r.t.=3.27 min [Waters HPLCwith PDA; Xterra RP18, 5.0 μm, 4.6×150 mm column; gradient of 70:30 H₂O(0.01 M ammonium bicarbonate):CH₃CN to 10:90 H₂O (0.01 M ammoniumbicarbonate):CH₃CN in 5.0 min and hold for 10.0 min with flow rate of1.0 mL/min].

Example 114N-(5-Cyanopyridin-2-yl)-N-methyl-3-(4-((2-(methylamino)ethyl)carbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound 114-1 was prepared using the general procedure described inAmide Coupling-Method 2 with the appropriate starting materials. Thepale red semi solid crude product was used as such for the next stepwithout further purification. ESI-LC/MS: m/z 405.29 (M+H); R_(t)=3.14min [Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 3.0 min and hold for 2.0 min with flow rate of 0.4mL/min].

Step 2

Compound 114-2 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. The yellowcolor semi solid crude product was used as such for the next stepwithout further purification. ESI-LC/MS: m/z 554.12 (M+H); R_(t)=2.68min [Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 3.0 min and hold for 2.0 min with flow rate of 0.4mL/min].

Step 3

A solution mixture ofN-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(2-(methylamino)ethylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide6 (350 mg) and dioxane.HCl (4M) (3.0 mL) in dioxane (10 mL) was stirredat room temperature for 1 h. The reaction mixture was diluted withdiethyl ether and filtered. The collected solid was dissolved in water,basified with sat. NaHCO₃ to pH 10 and extracted with 10% methanol inchloroform. The combined organic extracts were dried over anhydrousNa₂SO₄ and concentrated. The crude compound was purified by prep-TLC toafford 60 mg (17% over three steps from SM) ofN-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(2-(methylamino)ethylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide114 as a yellow color solid. ¹H-NMR (400 MHz, CD₃OD): δ 8.71 (d, J=1.8Hz, 1H), 8.53 (d, J=6.6 Hz, 1H), 8.34 (s, 1H), 8.04 (dd, J=2.2, 8.8 Hz,1H), 7.93-7.98 (m, 3H), 7.62 (d, J=8.4 Hz, 2H), 7.49 (d, J=7.9 Hz, 1H),6.87 (dd, J=2.2, 7.4 Hz, 1H), 3.59-3.61 (m, 5H), 2.90-2.91 (m, 2H), 2.54(s, 3H). ESI-LC/MS: m/z 454.18 (M+H); R_(t)=1.85 min [Waters AcquityUPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) holdfor 0.5 minute and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0min and hold for 2.0 min with flow rate of 0.4 mL/min]. HPLC purity:95.2% at 295 nm; R_(t)=2.40 min [Waters Acquity UPLC with PDA; WatersAcquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 90:10 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4.0 min and hold for 2.0 min with flow rate of 0.3 mL/min].

Example 115N-(5-cyanopyridin-2-yl)-3-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound 115-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield59%. Off-white solid. ¹H NMR (DMSO-d₆): δ 8.47 (br. s, 1H), 7.77 (d,J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 3.33-3.35 (m, 2H), 2.41 (t, J=7.0Hz, 2H), 2.18 (s, 6H). ESI-LC/MS: m/z 270.99 (M+H) & 273.07 [(M+2)+H];R_(t)=1.64 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min].

Step 2

To a stirred solution of 4-bromo-N-(2-(dimethylamino)ethyl)benzamide115-1 (1.0 g, 3.703 mmol), bis(pinacolato)diboron (1.12 g, 4.44 mmol),KOAc (1.08 g, 11.109 mmol) in N,N-dimethylacetamide (40 mL) was degassedwith argon for about 15 min. PdCl₂(dppf)CH₂Cl₂(91 mg, 0.111 mmol) wasadded under argon atmosphere. The resulting reaction mixture wasmaintained at 100° C. for 16 h. The reaction mixture was cooled to roomtemperature, water (50 mL) was added to reaction mass and filteredthrough celite. The filtrate was distilled under reduced pressure toafford 1.8 g (crude) of 4-(2-(dimethylamino)ethylcarbamoyl)phenylboronicacid 115-3 as brown semi solid. The crude product was used as such fornext reaction.

Step 3

Compound 115 was prepared using the general procedure described inSuzuki procedure G with the appropriate starting materials. Yield 3%(over two steps). Yellow color solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.85(d, J=3.2 Hz, 1H), 8.72 (d, J=7.0 Hz, 1H), 8.53 (s, 1H), 8.45 (br. s,1H), 8.25 (dd, J=2.2, 8.8 Hz, 1H), 7.99 (s, 1H), 7.92 (d, J=8.3 Hz, 2H),7.61-7.68 (m, 3H), 6.84 (dd, J=1.3, 7.0 Hz, 1H), 3.53 (s, 3H), 3.37-3.41(m, 2H), 2.44 (m, 2H), 2.32 (br s, 6H). ESI-LC/MS: m/z 468.18 (M+H);R_(t)=1.86 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min]. HPLC purity: >99% at 254 nm; R_(t)=1.34 min [WatersAcquity UPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0 min withflow rate of 0.3 mL/min].

Example 116N-(4-Chlorophenyl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 1-bromo-4-chlorobenzene (300 mg, 1.57 mmol) andt-BuONa (226 mg, 2.35 mmol) in toluene (3.0 mL) was degassed with argonfor about 10 min. Pd₂(dba)₃ (14 mg, 0.015 mmol), BINAP (29 mg, 0.04mmol) and cyclopropylamine (0.179 mL, 2.58 mmol) were added under argonatmosphere. The resulting reaction mixture was maintained at 80° C. for24 h. The reaction mixture was diluted with water and extracted withethyl acetate (2×50 mL). The combined organic layer was washed withwater, brine solution, dried over anhydrous Na₂SO₄ and concentrated. Thecrude product was purified by column chromatography over silica-gel(100-200 mesh) using a solvent gradient mixture of 0.5% ethyl acetate inpet-ether to afford 50 mg (19%) of 4-chloro-N-cyclopropylaniline 116-1as a pale yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ7.12 (d, J=8.8 Hz,2H), 6.70 (d, J=8.8 Hz, 2H), 4.16 (br. s, 1H), 2.37-2.40 (m, 1H),0.70-0.75 (m, 2H), 0.48-0.51 (m, 2H).

Step 2

Compound 116-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield37%. Off white solid. ¹H NMR (400 MHz, DMSO-d₆): b 8.69 (d, J=6.8 Hz,1H), 8.20 (s, 1H), 7.65 (s, 1H), 7.36-7.42 (m, 4H), 6.98 (d, J=6.8 Hz,1H), 3.28-3.32 (m, 1H), 0.73-0.74 (m, 2H), 0.52-0.54 (m, 2H). ESI-LC/MS:m/z 391.6 (M+H); R_(t)=3.14 min [Waters Acquity UPLC with Quattro-microdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.5 min and hold for 1.5 min withflow rate of 0.4 mL/min]

Step 3

Compound 116 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 20%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): b 8.71 (d, J=7.0 Hz, 1H),8.45-8.48 (m, 2H), 7.92-7.96 (m, 3H), 7.63 (d, J=7.9 Hz, 2H), 7.38-7.45(m, 4H), 7.00 (d, J=6.6 Hz, 1H), 3.28-3.20 (m, 1H), 2.82 (d, J=4.4 Hz,3H), 0.75-0.80 (m, 2H), 0.53-0.57 (m, 2H). ESI-LC/MS: m/z 445.14 (M+H) &446.92 [(M+2)H+]; R_(t)=2.61 min [Waters Acquity UPLC with Quattro microTQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2 min with flowrate of 0.4 mL/min]. HPLC Purity: 97.3% at 254 nm; R_(t)=2.87 min[Waters Acquity UPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm,2.1×100 mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA)to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 minwith flow rate of 0.3 mL/min].

Example 117N-(5-Cyanopyridin-2-yl)-N-(cyclopropylmethyl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 2-bromo-5-cyanopyridine (1.0 g, 5.46 mmol),cyclopropylmethylamine (0.939 mL, 10.95 mmol) and in dioxane (20 mL) wasstirred at 100° C. for 16 h in sealed tube. Distilled off the volatilesand the crude residue was passed through silica-gel (100-200 mesh)column with 20% ethyl acetate in pet-ether as eluant to gave 900 mg(95%) of 6-(cyclopropylmethylamino)nicotinonitrile 117-1 as an off-whitesolid. ESI-LC/MS: m/z 174.0 (M+H); R_(t)=3.52 min [Agilent LC with Iontrap Detector; Xterra MS-C18, 2.5 μm, 4.6×50 mm column; gradient of80:20 H₂O (0.01 M ammonium bicarbonate):CH₃CN to 10:90 H₂O (0.01 Mammonium bicarbonate):CH₃CN in 4.0 min and hold for 3.0 min with flowrate of 1.0 mL/min].

Step 2

Compound 117-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Thecrude (500 mg) compound was used directly for next reaction. ESI-LC/MS:m/z 396.00 (M+H) & 398.00 [(M+2)+H]; R_(t)=2.98 min [Waters Acquity UPLCwith Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and holdfor 2 min with flow rate of 0.4 mL/min].

Step 3

Compound 117 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 20%(over two steps yield). Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ8.88(d, J=2.2 Hz, 1H), 8.67 (d, J=7.5 Hz, 1H), 8.51 (s, 1H), 8.45-8.48 (m,1H), 8.24 (dd, J=2.2, 6.2 Hz, 1H), 7.90-7.94 (m, 3H), 7.51-7.61 (m, 3H),6.75 (dd, J=1.8, 5.7 Hz, 1H), 3.99 (d, J=6.0 Hz, 2H), 2.82 (d, J=4.4 Hz,3H), 1.15-1.22 (m, 1H), 0.38-0.42 (m, 2H), 0.17-0.21 (m, 2H). ESI-LC/MS:m/z 451.28 (M+H); R_(t)=2.49 min [Waters Acquity UPLC with Quattro microTQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2 min with flowrate of 0.4 mL/min]. HPLC purity: 97.2% at 254 nm; R_(t)=1.30 min[Waters Acquity UPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm,2.1×100 mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA)to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 minwith flow rate of 0.3 mL/min].

Example 118N-(4-Cyanophenyl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A mixture of 4-fluorobenzonitrilre (1.0 g, 8.264 mmol), cyclopropylamine(20 mL) and K₂CO₃ (3.42 g, 24.745 mmol) in DMSO (10 mL) was stirred at120° C. for 90 min under MW irradiation. The reaction mixture waspartitioned between water (50 mL) and ethyl acetate (100 mL). Thecombined organic layer was washed with brine (100 mL), dried overanhydrous Na₂SO₄ and concentrated to afford 650 mg (50%) of4-(cyclopropylamino)benzonitrile 118-1 as a white solid. ¹H NMR (400MHz, DMSO-d₆): 7.47 (d, J=7.6 Hz, 2H), 7.05 (s, 1H), 6.75 (d, J=7.2 Hz,2H), 2.28-2.40 (m, 1H), 0.72-0.76 (m, 2H), 0.38-0.44 (m, 2H).

Step 2

Compound 118-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield13%. Yellow solid. ESI-LC/MS: m/z 380.99 (M+H) & 382.97 [(M+2)+H];R_(t)=2.77 min [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4mL/min].

Step 3

Compound 118 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 44%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.75 (d, J=7.4 Hz, 1H), 8.51(s, 1H), 8.42-8.50 (br.s, 1H), 8.07 (s, 1H), 7.93 (d, J=8.3 Hz, 2H),7.88 (d, J=8.8 Hz, 2H), 7.62-7.70 (m, 4H), 7.05 (d, J=7.4 Hz, 1H),3.30-3.37 (m, 1H), 2.82 (d, J=4.0 Hz, 3H), 0.80-0.83 (m, 2H), 0.77-0.79(m, 2H). ESI-LC/MS: m/z 436.11 (M+H); R_(t)=2.35 min [Waters AcquityUPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and holdfor 2 min with flow rate of 0.4 mL/min]. HPLC purity: 98.0% at 254 nm;R_(t)=2.15 min [Waters Acquity UPLC with PDA detector; Waters AcquityBEH C18, 1.7 μm, 2.1×100 mm column; gradient of 50:50 H₂O (0.025%TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in4 min and hold for 2 min with flow rate of 0.3 mL/min].

Example 119N-(tert-Butyl)-N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 2-bromo-5-cyanopyridine (1.0 g, 5.46 mmol) andt-butylamine (2.0 g, 27.39 mmol) in THF (10 mL) was stirred at 100° C.for 20 h in sealed tube. The reaction mixture was partitioned betweenwater (50 mL) and ethyl acetate (100 mL). The ethyl acetate was washedwith brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated toafford 400 mg of crude 6-(tert-butylamino)nicotinonitrile 119-1 as awhite solid. The crude product was used as such for the next stepwithout further purification.

Step 2

Compound 119-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield30% (over two steps). Brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.91 (d,J=1.7 Hz, 1H), 8.54-8.56 (m, 1H), 8.26 (dd, J=2.6, 8.3 Hz, 1H), 8.14 (s,1H), 7.73 (d, J=8.3 Hz, 1H), 7.28 (s, 1H), 6.73 (dd, J=1.8, 7.0 Hz, 1H),1.47 (s, 9H). ESI-LC/MS: m/z 398.06 (M+H) & 400.04 [(M+2)+H]; R_(t)=2.94min. [Waters Acquity UPLC with Quattro micro TQD; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 minutes to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 minutes and hold for 2 minutes with flow rate of 0.4mL/min].

Step 3

Compound 119 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 30%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.96 (s, 1H), 8.58 (d, J=6.6Hz, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.29 (d, J=7.9 Hz, 1H), 7.97 (d,J=7.0 Hz, 2H), 7.77 (d, J=7.4 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J=7.5 Hz,2H), 6.76 (d, J=7.4 Hz, 1H), 2.82 (s, 3H), 1.47 (s, 9H). ESI-LC/MS: m/z453.19 (M+H); R_(t)=2.43 min. [Waters Acquity UPLC with Quattro microTQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2 min with flowrate of 0.4 mL/min]. HPLC purity: 98.4% at 282 nm; R_(t)=2.492 min.[Waters Acquity UPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm,2.1×100 mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA)to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 minwith flow rate of 0.3 mL/min].

Example 1203-(4-Carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide

Compound 120 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 29%.Yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.84 (d, J=1.8 Hz, 1H), 8.74(d, J=7.1 Hz, 1H), 8.53 (s, 1H), 8.37 (dd, J=2.2, 8.8 Hz, 1H), 8.02 (br.s, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.3 Hz, 1H), 7.64 (d, J=8.3Hz, 2H), 7.40 (s, 1H), 7.00 (dd, J=1.8, 7.5 Hz, 1H), 3.24-3.30 (m, 1H),0.85-90 (m, 2H), 0.65-0.67 (m, 2H). ESI-LC/MS: m/z 423.25 (M+H);R_(t)=2.39 min [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4mL/min]. HPLC purity=98.4% at 254 nm; R_(t)=1.72 min [Waters AcquityUPLC with PDA detector; Waters Acquity HSS C18, 1.8 μm, 2.1×100 mmcolumn; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 min withflow rate of 0.4 mL/min].

Example 121N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(isopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound 121-1 was prepared using the general procedure described inAmide Coupling-Method 2 with the appropriate starting materials. Yield220 mg (crude). Off-white solid. The crude product was used as such forthe next step without further purification. ESI-LC/MS: m/z 290.22 (M+H);R_(t)=2.88 min. [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4mL/min].

Step 2

Compound 121 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 1%(over two steps). yellow solid. ¹H-NMR (400 MHz, CD₃OD): δ 8.67 (d,J=2.2 Hz, 1H), 8.55 (d, J=7.0 Hz, 1H), 8.34 (s, 1H), 8.18 (dd, J=2.2,8.3 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.75 (d, J=8.8 Hz,1H), 7.63 (d, J=8.4 Hz, 2H), 6.98 (dd, J=1.8, 7.1 Hz, 1H), 4.22-4.30 (m,1H), 2.82 (br. s, 1H), 1.28 (d, J=6.6 Hz, 6H), 0.96-1.00 (m, 2H),0.69-0.73 (m, 2H). ESI-LC/MS: m/z 465.19 (M+H); R_(t)=2.73 min [WatersAcquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm,2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA)hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 minand hold for 2 min with flow rate of 0.4 mL/min]. HPLC purity=98.4% at290 nm; R_(t)=1.41 min [Waters Acquity UPLC with PDA detector; WatersAcquity HSS C18, 1.8 μm, 2.1×100 mm column; gradient of 50:50 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4 min and hold for 2 min with flow rate of 0.4 mL/min].

Example 122N-(6-Methoxypyridin-3-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution of 5-bromo-2-nitropyridine (5.0 g, 24.63 mmol), in methanol(100 mL) was added sodium methoxide (2.67 g, 49.44 mmol) and stirred at75° C. for 2 h. The reaction mixture was diluted with water (150 mL) andextracted with ethyl acetate (2×200 mL). The combined extracts werewashed with water (200 mL), brine (200 mL), dried over anhydrous Na₂SO₄and concentrated. The crude compound was purified by columnchromatography over silica gel (100-200 mesh) using a solvent gradientmixture of 5% ethyl acetate in pet-ether as eluant to afford 2.5 g (54%)of 5-bromo-2-methoxypyridine 122-1 as a colorless liquid. ¹H NMR (400MHz, CDCl₃): b 8.19 (d, J=2.2 Hz, 1H), 7.63 (dd, J=1.8, 8.8 Hz, 1H),6.66 (d, J=8.7 Hz, 1H), 3.90 (s, 3H). ESI-LC/MS: m/z 190.13 [(M+2)H+];R_(t)=3.13 min [Agilent LC with Ion trap Detector; Waters Symmetry C18,3.5 μm, 4.6×75 mm column; gradient of 50:50 H₂O (0.1% HCOOH):CH₃CN (0.1%HCOOH) to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 4 min and holdfor 3 min with flow rate of 1.0 mL/min].

Step 2

A solution mixture of 5-bromo-2-methoxypyridine (1.2 g, 6.38 mmol), 40%methylamine in water (20 mL) and CuSO₄. 5H₂O (320 mg, 1.28 mmol) inethanol (10 mL) was stirred at 100° C. for 5 h. The reaction mixture waspartitioned between water (50 mL) and ethyl acetate (3×50 mL). Thecombined ethyl acetate layer was washed with brine (100 mL), dried overanhydrous Na₂SO₄ and concentrated to afford 800 mg (91%) of6-methoxy-N-methylpyridin-3-amine 122-2 as a pale brown solid. ¹H NMR(400 MHz, CDCl₃): b 7.56 (d, J=3.1 Hz, 1H), 6.98 (dd, J=2.6, 8.8 Hz,1H), 6.63 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 3.37 (br.s, 1H), 2.87 (s,3H). ESI-LC/MS: m/z 139.06 (M+H); R_(t)=0.59 min [Waters Acquity UPLCwith Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and holdfor 2 min with flow rate of 0.4 mL/min].

Step 3

Compound 122-3 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield87%. Pale brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (s, 1H), 8.18(s, 1H), 8.07 (s, 1H), 7.79 (dd, J=2.2, 8.7 Hz, 1H), 7.50 (s, 1H),6.79-6.81 (m, 2H), 3.75 (m, 3H), 3.36 (s, 3H). ESI-LC/MS: m/z 360.98(M+H) & 363.05 [(M+2)+H]; R_(t)=2.47 min [Waters Acquity UPLC withQuattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column;gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 minto 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2min with flow rate of 0.4 mL/min.

Step 4

Compound 122 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 13%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.63-8.65 (m, 1H), 8.44-8.52(m, 2H), 8.11 (s, 1H), 7.82-7.93 (m, 4H), 7.56-7.64 (m, 2H), 6.83-6.85(d, J=8.8 Hz, 2H), 3.75 (s, 3H), 3.38 (s, 3H), 2.81 (d, J=4.4 Hz, 3H).ESI-LC/MS: m/z 416.20 (M+H); R_(t)=2.28 min [Waters Acquity UPLC withQuattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column;gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 minto 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2min with flow rate of 0.4 mL/min]. HPLC purity: 98.9% at 290 nm;R_(t)=1.81 min [Waters Acquity UPLC with PDA detector; Waters AcquityBEH C18, 1.7 μm, 2.1×100 mm column; gradient of 70:30 H₂O (0.025%TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in4 min and hold for 2 min with flow rate of 0.3 mL/min].

Example 123N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(cyclopropylcarbamoyl)phenyl)pyrazolo[1,5a]pyridine-5-carboxamide

Step 1

Compound 123-1 was prepared using the general procedure described inAmide Coupling-Method 2 with the appropriate starting materials. Thecrude colorless gum product was used as such for next step withoutfurther purification. ESI-LC/MS: m/z 288.4 (M+H); R_(t)=4.47 min[Agilent LC with Ion trap Detector; Waters Symmetry C18, 3.5 μm, 4.6×75mm column; gradient of 80:20 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) holdfor 1 minutes to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 4 min andhold for 3 min with flow rate of 1.0 mL/min].

Step 2

Compound 123 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 6.5%(over two steps). Yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (d,J=1.8 Hz, 1H), 8.74 (d, J=7.5 Hz, 1H), 8.52 (s, 1H), 8.49 (d, J=4.0 Hz,1H), 8.36 (dd, J=2.2, 8.3 Hz, 1H), 8.03 (brs, 1H), 7.91 (d, J=8.3 Hz,2H), 7.82 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.00 (d, J=5.8 Hz,1H), 3.20-3.26 (m, 1H), 2.84-2.90 (m, 1H), 0.89-0.90 (m, 2H), 0.55-0.74(m, 6H). ESI-LC/MS: m/z 463.21 (M+H); R_(t)=2.40 min [Waters AcquityUPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and holdfor 2 min with flow rate of 0.4 mL/min]. HPLC purity=97.1% at 234 nm;R_(t)=2.46 min [Waters Acquity UPLC with PDA detector; Waters AcquityBEH C18, 1.7 μm, 2.1×100 mm column; gradient of 70:30 H₂O (0.025%TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in4 min and hold for 2 min with flow rate of 0.3 mL/min].

Example 124N-(5-Chloropyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A mixture of 2-bromo-5-chloropyridine (2.0 g, 10.392 mmol),cyclopropylamine (3.62 mL, 52.249 mmol) and DIPEA (9.12 mL, 52.36 mmol)in NMP (20 mL) was stirred at 160° C. for 2 h under MW irradiation. Thereaction mixture was partitioned between water (2×100 mL) and ethylacetate (100 mL). The ethyl acetate was washed with brine (100 mL),dried over anhydrous Na₂SO₄ and concentrated. The crude compound waspurified by column chromatography over silica-gel (100-200 mesh) using asolvent gradient of 4% ethyl acetate in chloroform as eluant to afford400 mg (23%) of 5-chloro-N-cyclopropylpyridin-2-amine 124-1 as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ7.98 (d, J=2.2 Hz, 1H),7.50 (dd, J=2.6, 8.8 Hz, 1H), 7.00 (s, 1H), 6.58 (d, J=8.8 Hz, 1H),2.45-2.48 (m, 1H), 0.66-0.69 (m, 2H), 0.38-0.41 (m, 2H). ESI-LC/MS: m/z169.0 (M+H) & 171.0 [(M+2)+H]; R_(t)=3.73 min [Agilent LC with Ion trapDetector; Waters Xterra MS-C18, 2.5 μm, 4.6×50 mm column; gradient of95:5 H₂O (0.01 M ammonium bicarbonate):CH₃CN to 20:80 H₂O (0.01 Mammonium bicarbonate):CH₃CN in 4 min and hold for 3 min with flow rateof 1.0 mL/min].

Step 2

Compound 124-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield61%. Pale brown solid. ¹H NMR (400 MHz, DMSO-d₆): b 8.68 (d, J=7.5 Hz,1H), 8.43 (d, J=2.6 Hz, 1H), 8.21 (s, 1H), 7.99 (dd, J=2.6, 8.3 Hz, 1H),7.55-7.57 (m, 2H), 6.90 (dd, J=1.7, 7.0 Hz, 1H), 3.20-3.22 (m, 1H),0.83-0.84 (m, 2H), 0.63-0.66 (m, 2H). ESI-LC/MS: m/z 393.2 [(M+2)+H];R_(t)=5.02 min [Agilent LC with Ion trap Detector; Waters Symmetry C18,3.5 μm, 4.6×75 mm column; gradient of 80:20 H₂O (0.1% HCOOH):CH₃CN (0.1%HCOOH) to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 4 min and holdfor 3 min with flow rate of 1.0 mL/min.

Step 3

Compound 124 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 18%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): b 8.71 (d, J=7.0 Hz, 1H),8.48-8.52 (m, 3H), 8.02 (dd, J=2.6, 8.3 Hz, 1H), 7.93 (d, J=8.3 Hz, 2H),7.88 (s, 1H), 7.57-7.64 (m, 3H), 6.95 (dd, J=1.8, 7.5 Hz, 1H), 3.21-3.25(m, 1H), 2.81 (d, J=4.4 Hz, 3H), 0.81-0.86 (m, 2H), 0.62-0.66 (m, 2H).ESI-LC/MS: m/z 446.13 (M+H); R_(t)=2.35 min [Waters Acquity UPLC withQuattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column;gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 minto 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2min with flow rate of 0.4 mL/min. HPLC purity: 98.7% at 284 nm;R_(t)=1.153 min [Waters Acquity UPLC with PDA detector; Waters AcquityHSS C18, 1.8 μm, 2.1×100 mm column; gradient of 50:50 H₂O (0.025%TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in4 min and hold for 2 min with flow rate of 0.4 mL/min].

Example 125N-Cyclopropyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5a]pyridine-5-carboxamide

Step 1

A solution mixture of 2-bromo-5-fluoropyridine (2.0 g, 11.36 mmol),t-BuONa (1.65 g, 17.17 mmol) and toluene (20.0 mL) in sealed tube wasdegassed with argon for 15 min. Then were added Pd₂(dba)₃ (105 mg, 0.114mmol), BINAP (214 mg, 0.343 mmol) and finally cyclopropylamine (1.59 mL,22.98 mmol). The reaction mixture was maintained at 80° C. for 4 h. Thereaction mixture was filtered through celite and washed with ethylacetate (50 mL). The filtrate was concentrated in-vacuo. The resultingcrude compound was passed through column silica-gel (100-200 mesh) usinga solvent gradient of 10% ethyl acetate in pet-ether as eluant to give1.4 g of crude N-cyclopropyl-5-fluoropyridin-2-amine 125-1 as a redcolor oil. The crude product was used as such for the next step withoutfurther purification. ESI-LC/MS: m/z 153.4 (M+H); R_(t)=4.00 min[Agilent LC with Ion trap Detector; Waters Symmetry C18, 3.5 μm, 4.6×75mm column; gradient of 80:20 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) to10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 4 min and hold for 3 minwith flow rate of 1.0 mL/min].

Step 2

Compound 125-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield19% (over two steps). Off white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.66(d, J=7.6 Hz, 1H), 8.39 (d, J=3.2 Hz, 1H), 8.19 (s, 1H), 7.79 (td,J=3.6, 8.8 Hz, 1H), 7.56 (dd, J=4.4, 8.8 Hz, 1H), 7.50 (s, 1H), 6.88(dd, J=1.6, 7.6 Hz, 1H), 3.18-3.31 (m, 1H), 0.79-0.85 (m, 2H), 0.62-0.66(m, 2H). ESI-LC/MS: m/z 377.2 [(M+2)+H]; R_(t)=2.44 min [Agilent LC withIon trap Detector; Waters Symmetry C18, 3.5 μm, 4.6×75 mm column;gradient of 90:10 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) to 10:90 H₂O (0.1%HCOOH):CH₃CN (0.1% HCOOH) in 4 min and hold for 3 min with flow rate of1.0 mL/min].

Step 3

Compound 125 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 35%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.70 (d, J=7.1 Hz, 1H),8.44-8.49 (m, 3H), 7.94 (d, J=8.4 Hz, 2H), 7.80-7.87 (m, 2H), 7.57-7.64(m, 3H), 6.93 (d, J=7.4 Hz, 1H), 3.21-3.24 (m, 1H), 2.82 (d, J=3.9 Hz,3H), 0.80-0.85 (m, 2H), 0.63-0.67 (m, 2H). ESI-LC/MS: m/z 430.24 (M+H);R_(t)=2.21 min [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4mL/min]. HPLC purity: 96.4% at 254 nm; R_(t)=2.00 min [Waters AcquityUPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 min withflow rate of 0.3 mL/min].

Example 126N-(5-Cyanopyridin-2-yl)-N-cyclopentyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 2-bromo-5-cyanopyridine (2.0 g, 10.92 mmol),cyclopentylamine (2.17 mL, 21.99 mmol) in dioxane (20 mL) was stirred at100° C. for 16 h. The reaction mixture was partitioned between water(100 mL) and ethyl acetate (100 mL). The ethyl acetate was washed withbrine (100 mL), dried over anhydrous Na₂SO₄ and concentrated. The crudecompound was passed through silica-gel (100-200 mesh) to afford 1.9 g(93%) of 6-(cyclopentylamino)nicotinonitrile 126-1 as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.37 (d, J=1.8 Hz, 1H), 7.59-7.61(m, 2H), 6.51 (d, J=8.8 Hz, 1H), 4.17 (br.s, 1H), 1.87-1.93 (m, 2H),1.60-1.69 (m, 2H), 1.53-1.59 (m, 2H), 1.40-1.45 (m, 2H). ESI-LC/MS: m/z188.18 (M+H); R_(t)=2.11 min [Waters Acquity UPLC with Quattro microTQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2 min with flowrate of 0.4 mL/min].

Step 2

Compound 126-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield59%). Pale brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (d, J=1.8 Hz,1H), 8.61 (d, J=7.5 Hz, 1H), 8.24 (dd, J=2.2, 8.4 Hz, 1H), 8.20 (s, 1H),7.55 (d, J=8.3 Hz, 1H), 7.38 (s, 1H), 6.71 (dd, J=1.8, 7.5 Hz, 1H),4.87-4.91 (m, 1H), 1.84-1.95 (m, 2H), 1.77-1.81 (m, 2H), 1.52-1.75 (m,4H). ESI-LC/MS: m/z 410.06 (M+H) & 412.11 [(M+2)+H]; R_(t)=2.44 min[Waters Acquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in2.5 min and hold for 2 min with flow rate of 0.4 mL/min].

Step 3

Compound 126 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 21%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.98 (d, J=2.2 Hz, 1H), 8.64(d, J=7.0 Hz, 1H), 8.48-8.50 (m, 2H), 8.27 (dd, J=2.2, 8.3 Hz, 1H), 7.94(d, J=8.3 Hz, 2H), 7.77 (s, 1H), 7.54-7.60 (m, 3H), 6.73 (dd, J=1.8, 7.5Hz, 1H), 4.90-4.96 (m, 1H), 2.83 (d, J=4.4 Hz, 3H), 1.95-1.97 (m, 2H),1.79-1.83 (m, 2H), 1.53-1.77 (m, 4H). ESI-LC/MS: m/z 465.26 (M+H);R_(t)=2.58 min [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4mL/min]. HPLC purity: 99.3% at 292 nm; R_(t)=1.57 min [Waters AcquityUPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 min withflow rate of 0.3 mL/min].

Example 127N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(ethylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound 127-1 was prepared using the general procedure described inAmide Coupling-Method 2 with the appropriate starting materials. Thecrude product was used as such for next step without furtherpurification. ESI-LC/MS: m/z 276.1 (M+H); R_(t)=3.86 min [Agilent LCwith Ion trap Detector; Waters Xterra C18, 2.5 μm, 4.6×150 mm column;gradient of 80:20 H₂O (0.01 M Ammonium bicarbonate):CH₃CN to 10:90 H₂O(0.01 M Ammonium bicarbonate):CH₃CN in 4 min and hold for 3 min withflow rate of 1.0 mL/min].

Step 2

Compound 127 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 1.3%(over two steps). Yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (d,J=2.2 Hz, 1H), 8.73 (d, J=7.0 Hz, 1H), 8.48-8.54 (m, 2H), 8.36 (dd,J=2.2, 8.8 Hz, 1H), 8.03 (brs, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.81 (d,J=8.3 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 6.99 (dd, J=1.8, 7.5 Hz, 1H),3.24-3.30 (m, 1H) 3.32 (m, 2H), 1.14 (t, J=1.7 Hz, 3H), 0.88-0.92 (m,2H), 0.63-0.67 (m, 2H). ESI-LC/MS: m/z 451.29 (M+H); R_(t)=2.38 min[Waters Acquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in2.5 min and hold for 2 min with flow rate of 0.4 mL/min]. HPLCpurity=97% at 214 nm; R_(t)=1.27 min [Waters Acquity UPLC with PDAdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of50:50 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 min with flow rate of0.3 mL/min].

Example 1286-(N-Cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamido)nicotinic acid

Step 1

To a solution of 6-chloronicotinic acid (2.0 g, 12.69 mmol) indichloromethane (20 mL) was added oxalyl chloride (2.0 mL, 23.27 mmol)followed by catalytic amount N,N-dimethylformamide at rt and stirred for2 h. The resultant volatiles were distilled-off under reduced pressureto afford residue of acid chloride. The acid chloride was dissolved indichloromethane (20 mL), and was added benzyl alcohol (1.44 mL, 13.92mmol). The resulting reaction mixture was stirred for overnight at rt.The reaction mixture was diluted with dichloromethane (100 mL), washedwith water (50 mL), brine (25 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyover silica-gel (100-200 mesh) with a gradient mixture of 10% ethylacetate in pet-ether to afford 1.2 g (crude) of benzyl6-chloronicotinate 128-1 as an off-white solid. The crude product wasused as such for next step without further purification. ESI-LC/MS: m/z248.4 (M+H); R_(t)=5.12 min [Agilent LC with Ion trap Detector; SymmetryC18, 3.5 μm, 4.6×75 mm column; gradient of 80:20 H₂O (1% HCOOH):CH₃CN(0.1% HCOOH) to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 4.0 min andhold for 3.0 min with flow rate of 1.0 mL/min].

Step 2

A solution mixture of benzyl 6-chloronicotinate 128-1 (1.20 g, 4.84mmol), cyclopropylamine (0.68 mL, 9.83 mmol) and K₂CO₃ (1.34 g, 9.71mmol) in DMSO (12 mL) was stirred at 100° C. for 6 h. The reactionmixture was partitioned between water (150 mL) and ethyl acetate (100mL). The ethyl acetate layer was washed with brine (100 mL), dried overanhydrous Na₂SO₄ and concentrated. The crude compound was purified bycolumn chromatography over silica-gel (100-200 mesh) using a solventgradient mixture of 10% ethyl acetate in chloroform as eluant to afford(700 mg, 20% over two steps) benzyl 6-(cyclopropylamino)nicotinate 128-2as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.62 (s, 1H), 7.93(d, J=7.9 Hz, 1H), 7.69 (s, 1H), 7.25-7.50 (m, 5H), 6.62 (d, J=7.9 Hz,1H), 5.28 (s, 2H), 2.60 (br.s, 1H), 0.66-0.80 (m, 2H), 0.40-0.51 (m,2H). ESI-LC/MS: m/z 269.14 (M+H); R_(t)=2.07 min [Waters Acquity UPLCwith Quattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min andhold for 2.0 min with flow rate of 0.4 mL/min].

Step 3

Compound 128-3 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield36%. Off-white solid. ESI-LC/MS: m/z 493.02 [(M+2)+H]; R_(t)=3.32 min[Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 3.0 min and hold for 2.0 min with flow rate of 0.4mL/min].

Step 4

Compound 128-4 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 45%.Yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.90 (d, J=2.2 Hz, 1H), 8.71(d, J=7.4 Hz, 1H), 8.42-8.55 (m, 2H), 8.37 (dd, J=2.2, 8.4 Hz, 1H),7.86-8.00 (m, 3H), 7.72 (d, J=8.4 Hz, 1H), 7.62 (d, J=7.9 Hz, 2H),7.34-7.50 (m, 5H), 6.97 (dd, J=1.3, 7.4 Hz, 1H), 5.33 (s, 2H), 3.20-3.25(m, 1H), 2.81 (d, J=4.4 Hz, 3H), 0.82-0.92 (m, 2H), 0.63-0.67 (m, 2H).ESI-LC/MS: m/z 546.18 (M+H); R_(t)=2.88 min [Waters Acquity UPLC withQuattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min andhold for 2.0 min with flow rate of 0.4 mL/min].

Step 5

A suspension ofbenzyl6-(N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamido)nicotinate128-4 (200 mg, 0.366 mmol) and Pd(OH)₂ (40 mg, 20% w/w) in ethanol (4.0mL) was hydrogenated in Parr hydrogenation at 50 psi of H₂ gas pressurefor 5 h at rt. The reaction mixture was filtered through celite, washedthe bed with ethanol, and then distilled off the solvent under reducedpressure. The crude compound was purified by column chromatography oversilica gel (100-200 mesh) using a solvent gradient of 5-10% methanol inchloroform as eluant to afford 50 mg (30%) of6-(N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamido)nicotinicacid 128 as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.81 (s, 1H),8.69 (d, J=7.7 Hz, 1H), 8.50-8.56 (m, 1H), 8.48 (s, 1H), 8.24 (d, J=7.9Hz, 1H), 7.91 (d, J=7.9 Hz, 2H), 7.83 (br.s, 1H), 7.52-7.58 (m, 3H),6.95 (d, J=7.0 Hz, 1H), 3.20-3.27 (m, 1H), 2.81 (d, J=4.4 Hz, 3H),0.83-0.88 (m, 2H), 0.62-0.68 (m, 2H). ESI-LC/MS: m/z 456.16 (M+H);R_(t)=1.94 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min]. HPLC purity=97.9% at 285 nm; R_(t)=1.57 min [WatersAcquity UPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0 min withflow rate of 0.3 mL/min].

Example 129N-(5-Carbamoylpyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

A suspension of6-(N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamido)nicotinicacid 128 (200 mg, 0.439 mmol), NH₄Cl (200 mg 3.739 mmol), HATU (183 mg,0.481 mmol) and DIPEA (0.337 mL, 1.938 mmol) in DMF (6.0 mL) was stirredat rt for 16 h. The reaction mixture was diluted with water (75 mL) andextracted with ethyl acetate (3×30 mL). The combined organic layer waswashed with brine (25 mL), dried over anhydrous Na₂SO₄ and concentrated.The crude compound was purified by pre-TLC and then prep-HPLC to afford(70 mg, 35%) ofN-(5-carbamoylpyridin-2-A-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide129 as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.81 (d, J=2.2 Hz,1H), 8.70 (d, J=7.4 Hz, 1H), 8.45-8.54 (m, 2H), 8.26 (dd, J=2.2, 8.4 Hz,1H), 8.11 (s, 1H), 7.89-7.96 (m, 3H), 7.56-7.65 (m, 4H), 6.94 (dd, J=1.7Hz, 7.5 Hz, 1H), 3.22-3.29 (m, 1H), 2.81 (d, J=4.4 Hz, 3H), 0.85-0.90(m, 2H), 0.64-0.68 (m, 2H). ESI-LC/MS: m/z 455.23 (M+H); R_(t)=1.82 min[Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 3.0 min and hold for 2.0 min with flow rate of 0.4mL/min]. HPLC purity=>99% at 254 nm; R_(t)=2.30 min [Waters Acquity UPLCwith PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0 min with flow rateof 0.3 mL/min].

Example 130N-Cyclopropyl-N-(3,4-difluorophenyl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 1-bromo-3,4-difluorobenzene (2 g, 10.362 mmol) andt-BuONa (1.5 g, 15.62 mmol) in toluene (20 mL) was degassed with argonfor about 10 min. Pd₂(dba)₃ (95 mg, 0.103 mmol), BINAP (194 mg, 0.311mmol), cyclopropylamine (1.18 mL, 17.05 mmol) were added under argonatmosphere and sealed the reaction vessel. The resulting reactionmixture was maintained at 80° C. for 4 h. The reaction mixture wascoiled to room temperature and partitioned between ethyl acetate (2×100mL) and water (100 mL). The combined organic layer was washed withwater, brine solution, dried over anhydrous Na₂SO₄ and concentrated toafford 2 g (quantitative) of N-cyclopropyl-3,4-difluoroaniline 130-1 asa thick brown liquid. The crude material was used further withoutpurification. ESI-LC/MS: m/z 170.13 (M+H); R_(t)=2.99 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA)in 3.0 min and hold for 2.0 min with flow rate of 0.4 mL/min].

Step 2

Compound 130-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield7.4% (over two steps). Pale yellow solid. ¹H NMR (400 MHz, CDCl₃): δ8.29 (d, J=7.4 Hz, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.04-7.14 (m, 2H),6.87-6.89 (m, 1H) 6.75 (d, J=7.4 Hz, 1H), 3.22-3.25 (m, 1H), 0.92-0.95(m, 2H), 0.61-0.63 (m, 2H). ESI-LC/MS: m/z 392.06 (M+H) & 394.04[(M+2)H+]; R_(t)=3.06 min [Waters Acquity UPLC with Quattro-microdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min withflow rate of 0.4 mL/min].

Step 3

Compound 130 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 15%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.74 (d, J=7.0 Hz, 1H),8.45-8.51 (m, 2H), 8.06 (s, 1H), 7.94 (d, J=7.9 Hz, 2H), 7.70 (d, J=8.30Hz, 2H), 7.63-7.67 (m, 1H), 7.41-7.48 (m, 1H), 7.25 (d, J=8.80 Hz, 1H),7.02 (d, J=6.60 Hz, 1H), 3.26-3.30 (m, 1H), 2.81 (d, J=4.40 Hz, 3H),0.73-0.78 (m, 2H), 0.55-0.60 (m, 2H). ESI-LC/MS: m/z 447.19 (M+H);R_(t)=2.55 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min. HPLC purity: 95.4% at 254 nm; R_(t)=2.60 min [WatersAcquity UPLC with PDA; Waters Acquity; UPLC; HSS-T3, 1.7 μm, 2.1×100 mmcolumn; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0 min withflow rate of 0.4 mL/min].

Example 131N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(oxetan-3-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

Compound 131-1 was prepared using the general procedure described inAmide Coupling-Method 2 with the appropriate starting materials. Thecrude (off-white solid) product was used as such for the next stepwithout further purification.

Step 2

Compound 131 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 4%(over two steps). Yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.14 (d,J=6.2 Hz, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.75 (d, J=7.4 Hz, 1H), 8.55(brs, 1H), 8.36 (dd, J=2.2, 8.8 Hz, 1H), 8.05 (brs, 1H), 7.98 (d, J=7.9Hz, 2H), 7.82 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.01 (d, J=7.0Hz, 1H), 5.01-5.06 (m, 1H), 4.79 (t, J=6.6 Hz, 2H), 4.62 (t, J=6.2 Hz,2H), 3.23-3.29 (m, 1H), 0.88-0.92 (m, 2H), 0.62-0.65 (m, 2H). ESI-LC/MS:m/z 479.24 (M+H); R_(t)=2.22 min [Waters Acquity UPLC with Quattro microTQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2 min with flowrate of 0.4 mL/min]. HPLC purity=98.9% at 214 nm; R_(t)=1.90 min [WatersAcquity UPLC with PDA detector; Waters Acquity HSS T3, 1.7 μm, 2.1×100mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 minwith flow rate of 0.4 mL/min].

Example 132N-Cyclopropyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution of 2-bromo-5-trifluoromethylpyridine (500 mg, 2.21 mmol) andCs₂CO₃ (216 mg, 0.662 mmol) in 1,4-dioxane (5 mL) was degassed withargon for about 10 min. Pd(OAc)₂ (29 mg, 0.129 mmol), BINAP (55 mg,0.883 mmol) and cyclopropylamine (0.18 mL, 2.60 mmol) were added underargon atmosphere. The resulting reaction mixture was maintained at 100°C. for 4 h. The reaction mixture was diluted with water (1×50 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layer waswashed with water, brine solution, dried over Na₂SO₄ and concentrated.The crude product was passed through a column of silica-gel (100-200mesh) using a solvent gradient mixture of 15% ethyl acetate in pet-etherto afford 200 mg (11%) ofN-cyclopropyl-5-(trifluoromethyl)pyridin-2-amine 132-1 as a yellowsolid. ¹H NMR (400 MHz, CDCl₃): 8.37 (s, 1H), 7.66-7.68 (m, 1H), 6.77(d, J=8.8 Hz, 1H), 5.33 (brs, 1H), 2.55-2.60 (m, 1H), 0.83-0.87 (m, 2H),0.58-0.65 (m, 2H); ESI-LC/MS: m/z 203.3 (M+H); R_(t)=2.87 min [AgilentLC with Ion trap Detector; Waters Symmetry C18, 3.5 μm, 4.6×75 mmcolumn; gradient of 80:20 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) hold for 1min to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 4 min and hold for 3min with flow rate of 1.0 mL/min]

Step 2

Compound 132-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Thecrude product (250 mg) was used as such for the next step withoutfurther purification. ESI-LC/MS: m/z 425.03 (M+H) & 427.01 [(M+2)+H];R_(t)=3.09 min [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4 mL/min]

Step 3

Compound 132 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 3.7%(over two steps). Yellow solid. ¹H-NMR (DMSO-d₆): δ 8.80 (s, 1H), 8.74(d, J=7.0 Hz, 1H), 8.51 (s, 1H), 8.46-8.48 (m, 1H), 8.31 (d, J=8.8 Hz,1H), 7.96 (s, 1H), 7.92 (d, J=8.40 Hz, 2H), 7.80 (d, J=8.40 Hz, 1H),7.60 (d, J=8.30 Hz, 2H), 7.02 (d, J=7.1 Hz, 1H), 3.28-3.34 (m, 1H), 2.81(d, J=4.40 Hz, 3H), 0.86-0.91 (m, 2H), 0.63-0.65 (m, 2H). ESI-LC/MS: m/z480.23 (M+H); R_(t)=2.55 min [Waters Acquity UPLC with Quattro microTQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 2 min with flowrate of 0.4 mL/min]. HPLC purity: 99.0% at 292 nm; R_(t)=2.61 min[Waters Acquity UPLC with PDA detector; Waters Acquity HSS T3, 1.7 μm,2.1×100 mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA)to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 minwith flow rate of 0.4 mL/min].

Example 133N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of3-bromo-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide93-2 (1.0 g, 2.617 mmol), bis(pinacolato)diboron (3.33 g, 13.110 mmol)and KOAc (900 mg, 9.183 mmol) in dioxane (80.0 mL) were taken in to aseal tube and degassed with argon for about 30 min. Then added Pd(PPh₃)₄(727 mg, 0.629 mmol) and the reaction mixture was maintained at 110° C.for 48 h. The reaction mixture was filtered through celite and washedwith ethyl acetate (100 mL). The filtrate was washed with water (50 ml),brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuo toobtain 1.7 g (crude) ofN-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide131-1 as a brown semi solid. The crude product was used as such for thenext step without further purification. ESI-LC/MS: m/z 430.31 (M+H);R_(t)=2.93 min [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4mL/min].

Step 2

A solution ofN-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide133-1 (900 mg, crude), N-methyl 6-bromonicotinamide (225 mg, 1.046 mmol)and 2M K₂CO₃ (4.194 mL, 4.194 mmol) in dioxane (80 mL) were degassedwith argon for 30 min, added trans-PdCl₂(PPh₃)₂ (140 mg, 0.209 mmol) andstirred at 90° C. in sealed tube for 16 h. Reaction mixture was filteredthrough celite and washed the celite bed with ethyl acetate (100 mL).The combined filtrate was evaporated and the residue was purified bycolumn chromatography over silica-gel (100-200 mesh) using a solventgradient of 5% methanol in chloroform as eluant to obtain semi-pureproduct. This semi-pure compound was further purified by prep-HPLC gave25 mg (1% over two steps) ofN-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide133 as yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.03 (d, J=1.7 Hz,1H), 8.85 (s, 1H), 8.80 (d, J=2 Hz, 1H), 8.64-8.75 (m, 1H), 8.58-8.62(m, 2H), 8.35 (dd, J=2.2, 8.3 Hz, 1H), 8.19 (dd, J=2.2, 8.4 Hz, 1H),7.99 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.03 (dd, J=1.8, 7.1 Hz,1H), 3.24-3.29 (m, 1H), 2.83 (d, J=4.4 Hz, 3H), 0.90-0.95 (m, 2H),0.66-0.68 (m, 2H). ESI-LC/MS: m/z 438.29 (M+H); R_(t)=2.25 min [WatersAcquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm,2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA)hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 minand hold for 2 min with flow rate of 0.4 mL/min]. HPLC purity=97.2% at254 nm; R_(t)=1.94 min [Waters Acquity UPLC with PDA detector; WatersAcquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 70:30 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4 min and hold for 2 min with flow rate of 0.3 mL/min].

Example 1343-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide

Compound 134 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 24%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.76 (d, J=7.1 Hz, 1H), 8.52(s, 1H), 8.04-8.10 (m, 2H), 7.98 (d, J=8.3 Hz, 2H), 7.89 (d, J=8.4 Hz,2H), 7.63-7.70 (m, 4H), 7.41 (s, 1H), 7.05 (d, J=7.4 Hz, 1H), 3.29 (m,1H), 0.78-0.80 (m, 2H), 0.52-0.58 (m, 2H). ESI-LC/MS: m/z 422.20 (M+H);R_(t)=2.44 min [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4mL/min]. HPLC purity: 98.3% at 254 nm; R_(t)=2.19 min [Waters AcquityUPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 min withflow rate of 0.3 mL/min].

Example 135 3-(4-Carbamoylphenyl)-N-cyclopropyl-N-(3,4-difluorophenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 135 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 18%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.74 (d, J=7.0 Hz, 1H), 8.52(s, 1H), 8.06 (d, J=10.1 Hz, 2H), 7.98 (d, J=7.9 Hz, 2H), 7.60-7.70 (m,3H), 7.41-7.49 (m, 2H), 7.26 (d, J=8.3 Hz, 1H), 7.03 (d, J=7.0 Hz, 1H),3.27-3.35 (m, 1H), 0.76-0.80 (m, 2H), 0.55-0.60 (m, 2H). ESI-LC/MS: m/z433.21 (M+H); R_(t)=2.62 min [Waters Acquity UPLC with Quattro-microdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min withflow rate of 0.4 mL/min]. HPLC purity: 98.2% at 254 nm; R_(t)=2.55 min[Waters Acquity UPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0min with flow rate of 0.3 mL/min.

Example 136N-Cyclopropyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 2-bromo-5-methylpyridine (500 mg, 2.906 mmol),t-BuONa (418 mg, 4.354 mmol) in toluene (20.0 mL) in sealed tube wasdegassed with argon for 15 min. Pd₂(dba)₃ (26 mg, 0.028 mmol), BINAP (54mg, 0.086 mmol) and cyclopropylamine (0.40 mL, 5.77 mmol) were added.The reaction mixture was maintained at 100° C. for 4 h and cooled toroom temperature. The reaction mixture was filtered through celite andwashed with ethyl acetate (50 mL). The filtrate was concentrated underreduced pressure to afford 450 mg of crudeN-cyclopropyl-5-methylpyridin-2-amine 136-1 as pale red oil. Thismaterial was used further without purification. ESI-LC/MS: m/z 149.0(M+H); R_(t)=3.44 min [Agilent LC with Ion trap Detector; Xterra MS C18,2.5 μm, 4.6×50 mm column; gradient of 80:20 H₂O (0.01 M ammoniumbicarbonate):CH₃CN to 10:90 H₂O (0.01 M ammonium bicarbonate):CH₃CN in4.0 min and hold for 3.0 min with flow rate of 1.0 mL/min].

Step 2

Compound 136-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield42% (over two steps). Yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.22-8.26(m, 2H), 7.90 (s, 1H), 7.57 (s, 1H), 7.45 (dd, J=2.2, 7.9 Hz, 1H), 7.02(d, J=8.0 Hz, 1H), 6.76 (dd, J=1.7, 7.4 Hz, 1H), 3.28-3.31 (m, 1H), 2.31(s, 3H), 0.91-0.96 (m, 2H), 0.69-0.73 (m, 2H). ESI-LC/MS: m/z 371.1(M+H) & 373.08 [(M+2)+H]; R_(t)=2.55 min [Waters Acquity UPLC withQuattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min andhold for 2.0 min with flow rate of 0.4 mL/min].

Step 3

Compound 136 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 35%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.67 (d, J=7.5 Hz, 1H),8.49-8.55 (m, 1H), 8.46 (s, 1H), 8.26 (s, 1H), 7.93 (d, J=8.4 Hz, 2H),7.73 (s, 1H), 7.67 (dd, J=2.2, 7.9 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.34(d, J=8.4 Hz, 1H), 6.93 (dd, J=1.8, 7.5 Hz, 1H), 3.18-3.22 (m, 1H), 2.82(d, J=4.4 Hz, 3H), 2.22 (s, 3H), 0.80-0.84 (m, 2H), 0.64-0.67 (m, 2H).ESI-LC/MS: m/z 426.28 (M+H); R_(t)=1.84 min [Waters Acquity UPLC withQuattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 80:20 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min withflow rate of 0.4 mL/min]. HPLC purity: 96.2% at 230 nm; R_(t)=2.91 min[Waters Acquity UPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0min with flow rate of 0.3 mL/min].

Example 137N-(4-Cyanophenyl)-N-cyclopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 137 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 31%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): i 8.92 (d, J=1.7 Hz, 1H), 8.82(d, J=6.8 Hz, 1H) 8.72-8.75 (m, 1H), 8.67 (s, 1H), 8.19-8.22 (m, 2H),8.10 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H),7.11 (dd, J=1.3, 5.7 Hz, 1H), 3.37-3.39 (m, 1H), 2.86 (d, J=4.8 Hz, 3H),0.75-0.80 (m, 2H), 0.50-0.54 (m, 2H). ESI-LC/MS: m/z 437.16 (M+H);R_(t)=2.38 min [Waters Acquity UPLC with Quattro micro TQD; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN(0.025% TFA) in 2.5 min and hold for 2 min with flow rate of 0.4mL/min]. HPLC purity: 97.0% at 214 nm; R_(t)=1.27 min [Waters AcquityUPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 50:50 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 min withflow rate of 0.3 mL/min].

Example 1383-(6-Carbamoylpyridin-3-yl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide

Compound 138 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 7%.Yellow solid. ¹H-NMR (400 MHz, CD₃OD): δ 8.81 (s, 1H), 8.60 (d, J=7.5Hz, 1H), 8.43 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.10-8.13 (m, 1H), 8.02(s, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.0Hz, 1H), 3.36-3.38 (m, 1H), 0.89-0.91 (m, 2H), 0.600.62 (m, 2H).ESI-LC/MS: m/z 423.1 (M+H); R_(t)=2.37 min [Agilent LC with Ion trapDetector; Agilent Zorbax RRHT SB C18, 1.8 μm, 2.1×50 mm column; gradientof 90:10 H₂O (0.1% FA):CH₃CN (0.1% HCOOH) hold for 0.5 min to 10:90 H₂O(0.1% HCOOH):CH₃CN (0.1% HCOOH) in 2.5 min and hold for 2 min with flowrate of 0.4 mL/min]. HPLC purity: 99.7% at 254 nm; R_(t)=2.09 min[Waters Acquity UPLC with PDA detector; Waters Acquity BEH C18, 1.7 μm,2.1×100 mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA)to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4 min and hold for 2 minwith flow rate of 0.3 mL/min].

Example 1393-(5-Carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide

A solution ofN-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide133-1 (2.0 g, crude), 6-bromonicotinamide (400 mg, 2.00 mmol) and 2MK₂CO₃ (8.0 mL, 8.0 mmol) in dioxane (80 mL) were degassed with argon for30 min, added trans-PdCl₂(PPh₃)₂ (280 mg, 0.40 mmol) and stirred at 90°C. in sealed tube for 16 h. Reaction mixture was filtered through celiteand washed the celite bed with ethyl acetate (100 mL). The combinedfiltrate was evaporated and the residue was purified by columnchromatography over silica-gel (100-200 mesh) using a solvent gradientof 5% methanol in chloroform as eluant to obtain semi-pure product. Thissemi-pure compound was further purified by prep-HPLC gave 10 mg (1.5%over two steps) of Preparation of3-(5-Carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide139 as yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.07 (d, J=1.7 Hz,1H), 8.85 (s, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.75 (d, J=7.1 Hz, 1H), 8.63(s, 1H), 8.36 (dd, J=2.6, 8.8 Hz, 1H), 8.23 (dd, J=2.2, 8.3 Hz, 1H),8.14 (s, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.58 (s,1H), 7.03 (dd, J=1.8, 7.5 Hz, 1H), 3.24-3.28 (m, 1H), 0.90-0.95 (m, 2H),0.66-0.68 (m, 2H). ESI-LC/MS: m/z 424.34 (M+H); R_(t)=2.02 min [WatersAcquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm,2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA)hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 minand hold for 2 min with flow rate of 0.4 mL/min]. HPLC purity=97.8% at254 nm; R_(t)=2.75 min [Waters Acquity UPLC with PDA detector; WatersAcquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 90:10 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4 min and hold for 2 min with flow rate of 0.3 mL/min].

Example 140N-(5-cyanopyridin-2-yl)-N-ethyl-3-(4-[N-methylsulfamoyl]phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

A mixture of3-bromo-N-(5-cyanopyridin-2-yl)-N-ethylpyrazolo[1,5-a]pyridine-5-carboxamideI-69 (100 mg, 0.270 mmol) in DME:H₂O (3:1) (4 mL),(4-[N-methylsulfamoyl]phenyl)boronic acid (87 mg, 0.405 mmol) and NaHCO₃(68 mg, 0.810 mmol) were added in to a 10 mL microwave vial and themixture was degassed with argon for about 10 min. To this mixture wasadded PdCl₂(dppf)dichloromethane adduct (11 mg, 0.014 mmol) and sealedit, subjected to microwave at 140° C. for 30 min. The reaction mixturewas diluted with ethyl acetate (20 mL) and filtered through celite. Thefiltrate was extracted with water (20 mL), brine (10 mL), dried overNa₂SO₄ and concentrated on rotavap to get brown residue. The residue waspurified by column chromatography (ISCO purification system, 12 gsilicagel column) with gradient mixture of 95% ethylacetate incyclohexane to 100% ethylacetate as eluant to afford 14 mg (11%) ofN-(5-cyanopyridin-2-yl)-N-ethyl-3-(4-(N-methylsulfamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide140 as a yellow color solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.87 (dd,J=0.63, 2.26 Hz, 1H), 8.70 (dd, J=0.82, 7.22 Hz, 1H), 8.57 (s, 1H), 8.24(dd, J=2.26, 8.53 Hz, 1H), 8.00-8.06 (m, 1H), 7.82-7.88 (m, 2H),7.76-7.81 (m, 2H), 7.54 (dd, J=0.63, 8.53 Hz, 1H), 7.49 (br. s., 1H),6.78 (dd, J=1.76, 7.15 Hz, 1H), 4.12 (q, J=6.94 Hz, 2H), 2.46 (s, 3H),1.21 (t, J=7.03 Hz, 3H). ESI-LC/MS: m/z 461.1 (M+H); R_(t)=0.82 min[Waters Acquity UPLC coupled with MS waters ZQ 2000; Acquity UPLC BEHC18 column, 1.7 μm, 2.1×50 mm; gradient of 98:2 H₂O (0.1% HCOOH):CH₃CNto 2:98 H₂O (0.1% HCOOH):CH₃CN for 2 minutes run time with 1.0 mL/minflow rate]. HPLC purity=97.6% at 254 nm; R_(t)=1.53 min [Waters AcquityUPLC equipped with a Acquity UPLC HSS T3 column, 1.8 μm, 2.1×50 mm;gradient of 95:5 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1% HCOOH):CH₃CNfor 2 min run time with 1.0 mL/min flow rate].

Example 141N-(4-Cyanophenyl)-N-cyclopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

To a stirred solution of 6-bromo-N-methylnicotinamide (200 mg, 0.93mmol), hexamethylditin (0.193 mL, 0.93 mmol) in 1,2-dimethoxyethane (20mL) was degassed with argon for about 15 min. Pd(PPh₃)₄ (54 mg, 0.04mmol) was added under argon atmosphere. The resulting reaction mixturewas maintained at 80° C. for 16 h, allowed to room temperature andresulting solution was added to a mixture3-bromo-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide118-2 (354 mg, 0.93 mmol) and Pd(PPh₃)₄ (54 mg, 0.04 mmol). Theresulting reaction mixture was stirred at 90° C. for 16 h. The reactionwas cooled and diluted with ethyl acetate (50 mL), washed with water(100 mL), brine (50 mL), dried over Na₂SO₄ and concentrated. The crudecompound was purified by column chromatography over silica-gel (100-200)mesh with a solvent gradient mixture of 1% methanol in chloroform aseluant and then prep-HPLC to afford 20 mg (5%) ofN-(4-cyanophenyl)-N-cyclopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide141 as a yellow color solid. ¹H-NMR (400 MHz, CD₃OD): δ 9.02 (d, J=2.2Hz, 1H), 8.69 (s, 1H), 8.62 (s, 1H), 8.57 (d, J=7.0 Hz, 1H), 8.16 (dd,J=2.2, 8.4 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.3 Hz, 2H), 7.54(d, J=8.8 Hz, 2H), 7.08 (dd, J=1.7, 7.0 Hz, 1H), 3.37-3.40 (m, 1H), 2.96(s, 3H), 0.89-0.94 (m, 2H), 0.61-0.65 (m, 2H). ESI-LC/MS: m/z 437.2(M+H); R_(t)=2.36 min [Agilent LC-MS Infinity; Waters Acquity UPLC HSST3, 1.8 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.05% HCOOH+3.75 mMammonium acetate):CH₃CN (0.05% HCOOH) hold for 0.5 min and to 10:90 H₂O(0.05% HCOOH+3.75 mM ammonium acetate):CH₃CN (0.05% HCOOH) in 3.0 minand hold for 2.0 min with flow rate of 0.4 mL/min]. HPLC purity: 98.2%at 254 nm; R_(t)=3.08 min [Waters Acquity UPLC with PDA; Waters AcquityUPLC BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in4.0 min and hold for 2.0 min with flow rate of 0.3 mL/min].

Example 1423-(5-Carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide

To a stirred solution of 6-bromonicotinamide (200 mg, 1.00 mmol),hexamethylditin (0.189 mL, 0.100 mmol) in 1,2-dimethoxyethane (20 mL)was degassed with argon for about 15 min. Pd(PPh₃)₄ (54 mg, 0.04 mmol)was added under argon atmosphere. The resulting reaction mixture wasmaintained at 80° C. for 16 h, allowed to room temperature and added toa mixture of3-bromo-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide118-2 (380 mg, 1.00 mmol) and Pd(PPh₃)₄ (54 mg, 0.04 mmol). Theresulting reaction mixture was stirred at 90° C. for 16 h. The reactionmass was diluted with ethyl acetate (50 mL), washed with water (100 mL),brine (50 mL), dried over Na₂SO₄ and concentrated. The crude compoundwas purified by column chromatography over silica-gel (100-200) meshwith a solvent gradient mixture of 1% methanol in chloroform as aneluant and then prep-HPLC to afford 25 mg (6%) of3-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide142 as a yellow color solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 9.08 (d, J=1.7Hz, 1H), 8.83 (s, 1H), 8.77 (d, J=7.4 Hz, 1H), 8.67 (s, 1H), 8.23 (dd,J=2.2, 8.3 Hz, 1H), 8.13 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.86 (d, J=8.3Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.57 (s, 1H), 7.13 (dd, J=1.7, 7.4 Hz,1H), 3.36-3.40 (m, 1H), 0.79-0.83 (m, 2H), 0.50-0.54 (m, 2H). ESI-LC/MS:m/z 422.79 (M+H); R_(t)=2.13 min [Waters Acquity UPLC with Quattro-microdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min withflow rate of 0.4 mL/min]. HPLC purity: 98.8% at 254 nm; R_(t)=2.93 min[Waters Acquity UPLC with PDA; Waters Acquity UPLC BEH C18, 1.7 μm,2.1×100 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA)to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0min with flow rate of 0.3 mL/min].

Example 143N-(4-Chlorophenyl)-N-cyclopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 143 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 11%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.91 (s, 1H), 8.73-8.78 (m,2H), 8.64 (s, 1H), 8.09-8.16 (m, 3H), 7.39-7.45 (m, 4H), 7.04 (d, J=6.5Hz, 1H), 3.31 (m, 1H), 2.85 (d, J=4.8 Hz, 3H), 0.75-0.80 (m, 2H),0.52-0.58 (m, 2H). ESI-LC/MS: m/z 446.46 (M+H) & 448.50 [(M+2)+H];R_(t)=2.63 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.5 min and hold for 1.5 min with flow rateof 0.4 mL/min]. HPLC purity: 98.5% at 254 nm; R_(t)=1.90 min [WatersAcquity UPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mmcolumn; gradient of 50:50 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0 min withflow rate of 0.3 mL/min].

Example 144N-(5-Cyanopyridin-2-yl)-N-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

A solution mixture of3-bromo-N-(4-cyanophenyl)-N-cyclobutylpyrazolo[1,5-a]pyridine-5-carboxamide112-2 (3.0 g, 7.57 mmol),N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(3.99 g, 15.229 mmol), K₂CO₃ (2.3 g, 16.66 mmol) in dioxane:water (3:1)(60.0 mL) were degassed with argon for about 15 min. PdCl₂(dppf).CH₂Cl₂complex (1.24 g, 1.518 mmol) was added to the reaction mixture underargon atmosphere. The reaction mixture was maintained at 100° C. for 2h, cooled to room temperature and filtered through celite. The filtratewas partitioned between water (100 mL) and ethyl acetate (100 mL). Theethyl acetate layer was washed with water, brine, dried over anhydrousNa₂SO₄ and concentrated. The crude compound was purified by columnchromatography over silica gel (100-200 mesh) using a solvent gradientof 70 ethyl acetate in pet-ether as eluant to afford 1.8 g (53%) ofN-(5-cyanopyridin-2-yl)-N-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide144 as a Light yellow color solid. ¹H-NMR (300 MHz, DMSO-d₆): δ 8.96 (d,J=2.4 Hz, 1H), 8.81 (s, 1H), 8.67-8.74 (m, 2H), 8.62 (s, 1H), 8.33 (dd,J=2.4 Hz, 8.1 Hz, 1H), 8.05-8.14 (m, 2H), 7.84 (s, 1H), 7.62 (d, J=8.4Hz, 1H), 6.79 (dd, J=1.5, 7.2 Hz, 1H), 4.90-4.95 (m, 1H), 2.86 (d, J=4.8Hz, 3H), 2.19-2.27 (m, 2H), 2.07-2.13 (m, 2H), 1.58-1.69 (m, 2H).ESI-LC/MS: m/z 452.39 (M+H); R_(t)=2.25 min [Waters Acquity UPLC withSQD; Waters Acquity UPLC BEH C18, 1.7 μm, 2.1×50 mm column; gradient of95:05 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) hold for 0.5 min and to 50:50H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 1.7 min and to 0:100 H₂O (0.1%HCOOH):CH₃CN (0.1% HCOOH) in 3.0 min and hold for 2.0 min with flow rateof 1.0 mL/min]. HPLC purity: 98.5% at 254 nm; R_(t)=2.05 min [WatersAcquity UPLC with PDA; Waters Acquity UPLC BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 98:02 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 10:90H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min and hold for 3.5 min withflow rate of 0.3 mL/min].

Example 145N-(4-Cyanophenyl)-N-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 4-fluorobenzonitrile (2.0 g, 16.52 mmol),cyclobutylamine (1.69 mL, 19.79 mmol) and K₂CO₃ (4.56 g, 33.00 mmol) inDMSO (20 mL) was stirred at 90° C. for 16 h. The reaction mixture waspartitioned between water (100 mL) and ethyl acetate (100 mL). The ethylacetate was washed with brine (100 mL) and dried over anhyd.

Na₂SO₄ and concentrated. The crude compound was purified by columnchromatography over silica-gel (100-200 mesh) with a gradient mixture of5% ethyl acetate in chloroform as an eluant to give 1.5 g (53%) of4-(cyclobutylamino)benzonitrile 145-1 as a off-white solid. ¹H NMR (400MHz, DMSO-d₆): δ 7.43 (d, J=8.8 Hz, 2H), 6.96 (d, J=6.1 Hz, 1H), 6.55(d, J=8.8 Hz, 2H), 3.84-3.92 (m, 1H), 2.32-2.34 (m, 2H), 1.71-1.84 (m,4H).

Step 2

Compound 145-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield41%. Off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.60 (d, J=6.8 Hz,1H), 8.17 (s, 1H), 7.84 (d, J=8.4, Hz, 2H), 7.45-7.55 (m, 3H), 6.81 (dd,J=1.6, 7.4 Hz, 1H), 4.86-4.91 (m, 1H), 2.13-2.19 (m, 2H), 1.78-1.89 (m,2H), 1.50-1.65 (m, 2H). ESI-LC/MS: m/z 394.57 (M+H) & 396.61 [(M+2)+H];R_(t)=2.97 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 2.0 min with flow rateof 0.4 mL/min].

Step 3

Compound 145 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 13%.Yellow color solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H), 8.66-8.73(m, 2H), 8.60 (s, 1H), 8.07-8.12 (m, 2H), 7.92 (s, 1H), 7.88 (d, J=8.3Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 6.88 (dd, J=1.8, 7.0 Hz, 1H), 4.89-4.95(m, 1H), 2.86 (d, J=4.8 Hz, 3H), 2.11-2.20 (m, 2H), 1.82-1.89 (m, 2H),1.57-1.67 (m, 2H). ESI-LC/MS: m/z 451.54 (M+H); R_(t)=2.53 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA)in 3.0 min and hold for 2.0 min with flow rate of 0.4 mL/min]. HPLCpurity: 97.5% at 233 nm; R_(t)=1.71 min [Waters Acquity UPLC with PDA;Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 50:50 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4.0 min and hold for 2.0 min with flow rate of 0.3 mL/min].

Example 146N-(4-Cyanophenyl)-N-isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 4-fluorobenzonitrilre (3.0 g, 24.79 mmol),isopropylamine (10 mL, 122.14 mmol) and K₂CO₃ (3.41 g, 24.72 mmol) inDMSO (10 mL) was stirred at 100° C. for 16 h. The reaction mixture waspartitioned between water (50 mL) and ethyl acetate (2×50 mL). The ethylacetate layer was washed with brine (100 mL), dried over anhydrousNa₂SO₄ and concentrated to afford 1.2 g (30%) of4-(isopropylamino)benzonitrile 146-1 as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 7.42 (d, J=8.8 Hz, 2H), 6.60 (d, J=8.8 Hz, 2H), 6.53 (d,J=7.4 Hz, 1H), 3.56-3.64 (m, 1H), 1.13 (d, J=6.6 Hz, 6H).

Step 2

Compound 146-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield34%. Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.59 (d, J=7.0 Hz, 1H),8.15 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.47 (s,1H), 6.83 (dd, J=1.4, 7.1 Hz, 1H), 4.85-4.88 (m, 1H), 1.17 (d, J=6.6 Hz,6H). ESI-LC/MS: m/z 383.38 (M+H) & 385.42 [(M+2)+H]; R_(t)=2.81 min[Waters Acquity UPLC with Quattro-micro detector; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN(0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%

Step 3

Compound 146 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 20%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H), 8.73 (d, J=4.4Hz, 1H), 8.66 (d, J=7.0 Hz, 1H), 8.59 (s, 1H), 8.06-8.13 (m, 2H), 7.91(s, 1H), 7.85 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.5 Hz, 1H), 6.90 (d, J=6.2Hz, 1H), 4.89-4.91 (m, 1H), 2.86 (d, J=4.8 Hz, 3H), 1.18 (d, J=6.6 Hz,6H). ESI-LC/MS: m/z 439.59 (M+H); R_(t)=2.42 min. [Waters Acquity UPLCwith Quattro micro TQD; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min and holdfor 2 min with flow rate of 0.4 mL/min]. HPLC purity=97.49% at 233 nm;R_(t)=1.53 min [Waters Acquity UPLC with PDA detector; Waters AcquityBEH C18, 1.7 μm, 2.1×100 mm column; gradient of 50:50 H₂O (0.025%TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in4 min and hold for 2 min with flow rate of 0.3 mL/min].

Example 1475-Cyano-N-cyclopropyl-N-(3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide

Step 1

A solution mixture of 5-bromopyrazolo[1,5-a]pyridine 94-2 (900 mg, 4.59mmol) and t-BuONa (661.2 mg, 6.88 mmol) in toluene (10 mL) was degassedwith argon for about 10 min. To this mixture were added Pd₂(dba)₃ (84mg, 0.091 mmol), BINAP (114.2 mg, 0.102 mmol) and cyclopropylamine (2mL, 28.87 mmol) under argon atmosphere. The resulting reaction mixturewas maintained at 90° C. for 2 h under microwave irradiation. Thereaction mixture was diluted with water (30 mL) and extracted with ethylacetate (2×50 mL). The combined organic layer was washed with water (30mL), brine (25 mL), dried over anhydrous Na₂SO₄ and concentrated. Thecrude product was purified by column chromatography over silica-gel(100-200 mesh) using a solvent gradient of 25% ethyl acetate inpet-ether to afford 500 mg (62%) ofN-cyclopropylpyrazolo[1,5-a]pyridin-5-amine 147-1 as a brown solid.¹H-NMR (400 MHz, CDCl₃): δ 8.18 (d, J=7.5 Hz, 1H), 7.78 (d, J=2.2 Hz,1H), 6.72 (d, J=2.6 Hz, 1H), 6.15-6.18 (m, 2H), 4.28 (s, 1H), 2.44-2.49(m, 1H), 0.78-0.80 (m, 2H), 0.54-0.58 (m, 1H). ESI-LC/MS: m/z 173.75(M+H); R_(t)=1.99 min [Waters Acquity UPLC with Quattro-micro detector;Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O(0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 3.5 min and hold for 1.5 min withflow rate of 0.4 mL/min].

Step 2

Compound 147-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield57%. Off-white solid. ESI-LC/MS: m/z 304.1 (M+H); R_(t)=3.04 min[Agilent LC with Ion trap Detector; Waters Xterra MS-C18, 2.5 μm, 4.6×50mm column; gradient of 80:20 H₂O (0.01 M Ammonium bicarbonate):CH₃CN to10:90 H₂O (0.01 M Ammonium bicarbonate):CH₃CN in 4 min and hold for 3min with flow rate of 1.0 mL/min].

Step 3

To a stirred solution of5-cyano-N-cyclopropyl-N-(pyrazolo[1,5-a]pyridin-5-yl)picolinamide 147-2(700 mg, 2.3 mmol) in aceotonitrile (10 mL) was added NBS (650 mg, 3.6mmol) at room temperature and stirred for 16 h. Ethyl acetate (50 mL)was added to reaction mixture, and the organic layer was washed withwater (25 mL), brine (25 mL), dried over anhyd. Na₂SO₄ and concentrated.The crude product was purified by silica (100-200 mesh) columnchromatography with a solvent gradient mixture of 25% ethyl acetate inpet-ether to afford 500 mg (56%) ofN-(3-bromopyrazolo[1,5-a]pyridin-5-yl)-5-cyano-N-cyclopropylpicolinamide147-3 as an off-white solid. ESI-LC/MS: m/z 381.65 (M+H) & 383.69[(M+2)+H]; R_(t)=2.57 min [Waters Acquity UPLC with Quattro-microdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.5 min and hold for 1.5 min withflow rate of 0.4 mL/min].

Step 4

Compound 147 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 9%.Yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.99 (s, 1H), 8.76 (d, J=7.6Hz, 1H), 8.46 (m, 3H), 7.90-7.95 (m, 4H), 7.63-7.65 (m, 2H), 7.05-7.07(m, 1H), 3.30 (m, 1H), 2.81 (d, J=4.4 Hz, 3H), 0.70-0.74 (m, 2H),0.55-0.60 (m, 2H). ESI-LC/MS: m/z 437.1 (M+H); R_(t)=3.90 min [AgilentLC with Ion trap Detector; Waters Xterra MS-C18, 2.5 μm, 4.6×50 mmcolumn; gradient of 95:5 H₂O (0.01 M Ammonium bicarbonate):CH₃CN to10:90 H₂O (0.01 M Ammonium bicarbonate):CH₃CN in 4 min and hold for 3min with flow rate of 1.0 mL/min]. HPLC purity=90.1% at 226 nm;R_(t)=7.97 min [Waters HPLC with PDA; Xtimate C-18, 5.0 μm, 4.6×250 mmcolumn; gradient of 80:20 H₂O (0.01 M Ammonium acetate):CH₃CN to 20:80H₂O (0.01 M Ammonium acetate):CH₃CN in 20.0 minutes with flow rate of1.0 mL/min].

Example 148N-(5-Cyanopyridin-2-yl)-N-isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 148 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 12%.Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.97 (d, J=1.7 Hz, 1H),8.77-8.80 (m, 2H), 8.68 (d, J=7.7 Hz, 1H), 8.62 (s, 1H), 8.26 (dd,J=2.7, 8.4 Hz, 1H), 8.05-8.13 (m, 2H), 7.83 (s, 1H), 7.54 (d, J=8.4 Hz,1H), 6.76 (dd, J=1.7, 7.4 Hz, 1H), 4.90-4.93 (m, 1H), 2.86 (d, J=4.8 Hz,3H), 1.32 (d, J=7.1 Hz, 6H). ESI-LC/MS: m/z 440.52 (M+H); R_(t)=2.36 min[Waters Acquity UPLC with Quattro micro TQD; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025%TFA) hold for 0.5 min to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in3.0 min and hold for 2 min with flow rate of 0.4 mL/min]. HPLCpurity=>99% at 254 nm; R_(t)=2.49 min [Waters Acquity UPLC with PDAdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×100 mm column; Gradient of70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 4 minutes and hold for 2 minutes with flowrate of 0.3 mL/min].

Example 149N-(5-Cyano-6-methoxypyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 2,6-dichloronicotinonitrile (1 g, 5.78 mmol) andcyclopropylamine (1.82 mL, 26.27 mmol) in acetonitrile (10 mL) wasstirred at room temperature for 16 h. The reaction mixture was dilutedwith water and extracted with ethyl acetate (2×50 mL). The combinedorganic layer was washed with water, brine solution, dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified bycolumn chromatography over silica-gel (100-200 mesh) using a solventgradient mixture of 5% ethyl acetate in pet-ether to afford 500 mg (45%)of 2-chloro-6-(cyclopropylamino)nicotinonitrile 149-1 as a off whitesolid. ¹H NMR (400 MHz, CDCl₃): δ 7.68 (d, J=8.4 Hz, 1H), 6.69 (d, J=8.8Hz, 1H), 5.68 (br. s, 1H), 2.57-2.58 (m, 1H), 0.84-0.92 (m, 2H),0.59-0.67 (m, 2H). ESI-LC/MS: m/z 194.0 (M+H) & 196.0 [(M+2)+H];R_(t)=2.69 min [Agilent LC-MS Infinity; ZORBAX RRHT SB-C18, 1.8 μm,2.1×50 mm column; gradient of 90:10 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH)hold for 0.5 min and to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 3.0min and hold for 2.0 min with flow rate of 0.4 mL/min].

Step 2

A solution mixture of 2-chloro-6-(cyclopropylamino)nicotinonitrile (350mg, 1.807 mmol) and sodium methoxide (979 mg, 18.13 mmol) in methanol(20 mL) was maintained at 80° C. for 16 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate (2×150 mL). Thecombined organic layer was washed with water, brine solution, dried overanhydrous Na₂SO₄ and concentrated crude to afford 200 mg (58%) of6-(cyclopropylamino)-2-methoxynicotinonitrile 149-2 as a off whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (s, 1H), 7.70 (br.s, 1H), 6.24(br.s, 1H), 3.88 (s, 3H), 3.31 (br.s, 1H), 0.71-0.76 (m, 2H), 0.46-0.49(m, 2H). ESI-LC/MS: m/z 189.69 (M+H); R_(t)=2.66 min [Waters AcquityUPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50mm column; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) holdfor 0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.5 minand hold for 1.5 min with flow rate of 0.4 mL/min].

Step 3

A solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic acid I-7 (500mg, 2.074 mmol) in dichloromethane (10 mL) was added oxalyl chloride(0.5 mL, 5.82 mmol) followed by catalytic amount dimethylformamide atroom temperature and stirred for 30 min. The resultant volatiles weredistilled-off under reduced pressure to afford residue of acid chloride.The acid chloride was dissolved in dichloromethane (5 mL) was added to amixture of NaH (60%) (829 mg, 20.708 mmol) and6-(cyclopropylamino)-2-methoxynicotinonitrile 149-2 (395 mg, 2.087 mmol)in THF at 0° C. The resulting reaction mixture was stirred for 30 min atroom temperature and diluted with ethyl acetate (50 mL). The organiclayer was washed with water, brine, dried over anhydrous Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyover silica-gel (100-200 mesh) using a solvent gradient mixture of 30%ethyl acetate in pet-ether to afford 300 mg (35%) of3-bromo-N-(5-cyano-6-methoxypyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide149-3 as an off white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.72 (d, J=2.4Hz, 1H), 8.24-8.26 (m, 2H), 7.69 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.98(dd, J=2.0, 7.2 Hz, 1H), 3.56 (s, 3H), 3.12-3.18 (m, 1H), 0.94-1.01 (m,2H), 0.73-0.77 (m, 2H). ESI-LC/MS: m/z 412.41 (M+H) & 414.46 [(M+2)+H];R_(t)=2.94 min [Waters Acquity UPLC with Quattro-micro detector; WatersAcquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.025%TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O (0.025%TFA):CH₃CN (0.025% TFA) in 3.5 min and hold for 1.5 min with flow rateof 0.4 mL/min].

Step 4

Compound 149 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 23%.Yellow color solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.75 (d, J=7.1 Hz, 1H),8.54 (s, 1H), 8.47-8.51 (m, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.09 (s, 1H),7.92 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 1H),6.98 (d, J=7.5 Hz, 1H), 3.59 (s, 3H), 3.16-3.18 (m, 1H), 2.80 (d, J=4.4Hz, 3H), 0.95-0.99 (m, 2H), 0.75-0.87 (m, 2H). ESI-LC/MS: m/z 467.50(M+H); R_(t)=2.46 min [Waters Acquity UPLC with Quattro-micro detector;Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of 90:10 H₂O(0.025% TFA):CH₃CN (0.025% TFA) hold for 0.5 min and to 10:90 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 3.5 min and hold for 1.5 min withflow rate of 0.4 mL/min]. HPLC purity: 95.6% at 254 nm; R_(t)=2.63 min[Waters Acquity UPLC with PDA; Waters Acquity BEH C18, 1.7 μm, 2.1×100mm column; gradient of 70:30 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to20:80 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 4.0 min and hold for 2.0min with flow rate of 0.3 mL/min].

Example 150N-(5-cyanopyridin-2-yl)-N-ethyl-3-(6-[methylcarbamoyl]pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 150 was prepared using the general procedure described inSuzuki Procedure I with the appropriate starting materials. Yield 63%.yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.83-8.91 (m, 2H), 8.70-8.76(m, 2H), 8.66 (s, 1H), 8.24 (dd, J=2.26, 8.53 Hz, 1H), 8.07-8.17 (m,2H), 8.01-8.06 (m, 1H), 7.54 (dd, J=1.6, 8.53 Hz, 1H), 6.81 (dd, J=1.76,7.15 Hz, 1H), 4.12 (q, J=7.03 Hz, 2H), 2.86 (d, J=4.89 Hz, 3H), 1.20 (t,J=7.2 Hz, 3H). ESI-LC/MS: m/z 425.8 (M+H); R_(t)=0.85 min [Agilent UHPLC1290 coupled with API 3200; Acquity UPLC BEH C18 column, 1.7 μm, 2.1×50mm; gradient of 98:2 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1%HCOOH):CH₃CN for 2 min run time with 1.0 mL/min flow rate]. HPLCpurity=>99% at 254 nm; R_(t)=1.44 min [Waters Acquity UPLC equipped witha Acquity UPLC HSS T3 column, 1.8 μm, 2.1×50 mm; gradient of 95:5 H₂O(0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1% HCOOH):CH₃CN for 2 min run timewith 1.0 mL/min flow rate].

Example 151N-(5-fluoropyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution mixture of 2-bromo-5-fluoropyridine (5.0 g, 28.40 mmol),t-BuONa (4.13 g, 43.02 mmol) in toluene (150 mL) was de-gassed withargon for 15 min. BINAP (622 mg, 0.999 mmol), Pd₂(dba)₃ (263 mg, 0.287mmol) and isopropylamine (3.75 mL, 45.93 mmol) were added and stirredthe reaction mixture at 90° C. for 4 h. The reaction mixture waspartitioned between water (100 mL) and ethyl acetate (100 mL). Theorganic layer was washed with water (100 mL), brine (50 mL) and driedover anhyd. Na₂SO₄ and concentrated. The crude was purified by columnchromatography over silica-gel (100-200 mesh) with a gradient mixture of10% ethyl acetate in pet-ether as eluant to afford (3.5 g, 80%) of5-fluoro-N-isopropylpyridin-2-amine 151-1 as a red color oil. ¹H NMR(400 MHz, DMSO-d₆): δ 7.90 (d, J=2.8 Hz, 1H), 7.27-7.32 (m, 1H),6.41-6.44 (m, 1H), 6.27 (d, J=7.5 Hz, 1H), 3.85-3.93 (m, 1H), 1.11 (d,J=7.0 Hz, 6H). ESI-LC/MS: m/z 155.0 (M+H); R_(t)=3.56 min [Agilent LCwith Ion trap Detector; Xterra MS-C18, 2.5 μm, 4.6×50 mm column;gradient of 80:20 H₂O (0.01 M ammonium bicarbonate):CH₃CN to 10:90 H₂O(0.01 M ammonium bicarbonate):CH₃CN in 5.0 min and hold for 2.0 min withflow rate of 1.0 mL/min].

Step 2

Compound 151-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield85%. Light yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (d, J=7.4 Hz,1H), 8.46 (d, J=3.1 Hz, 1H), 8.14 (s, 1H), 7.64-7.69 (m, 1H), 7.34-7.40(m, 1H), 7.26 (s, 1H), 6.71 (dd, J=1.7, 7.0 Hz, 1H), 4.81-4.88 (m, 1H),1.21 (d, J=6.5 Hz, 6H). ESI-LC/MS: m/z 377.1 (M+H) & 379.1 [(M+2)+H];R_(t)=2.85 min [Agilent LC-MS Infinity; Waters Acquity UPLC HSS T3, 1.8μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.05% HCOOH+3.75 mMammonium acetate):CH₃CN (0.05% HCOOH) hold for 0.5 min and to 10:90 H₂O(0.05% HCOOH+3.75 mM ammonium acetate):CH₃CN (0.05% HCOOH) in 3.0 minand hold for 2.0 min with flow rate of 0.4 mL/min].

Step 3

Compound 151 was prepared using the general procedure described inSuzuki Coupling Procedure H with the appropriate starting materials.Yield 17%. Yellow solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.62 (d, J=6.4 Hz,1H), 8.54 (d, J=3.2 Hz, 1H), 8.45-8.48 (m, 1H), 8.44 (s, 1H), 7.94 (d,J=8.4 Hz, 2H), 7.73 (td, J=3.2, 8.4 Hz, 1H), 7.67 (s, 1H), 7.54 (d,J=8.0 Hz, 2H), 7.44 (dd, J=4.4, 8.8 Hz, 1H), 6.77 (dd, J=1.2, 6.8 Hz,1H), 4.88-4.92 (m, 1H), 2.82 (d, J=4.8 Hz, 3H), 1.24 (d, J=6.8 Hz, 6H).ESI-LC/MS: m/z 432.40 (M+H); R_(t)=2.16 min [Waters Acquity UPLC withQuattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.025% TFA):CH₃CN (0.025% TFA) hold for0.5 min and to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min andhold for 2.0 min with flow rate of 0.4 mL/min]. HPLC purity: 98.8% at254 nm; R_(t)=1.97 min [Waters Acquity UPLC with PDA; Waters Acquity BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 98:02 H₂O (0.025% TFA):CH₃CN(0.025% TFA) to 10:90 H₂O (0.025% TFA):CH₃CN (0.025% TFA) in 2.5 min andhold for 3.5 min with flow rate of 0.3 mL/min].

Example 152N-Isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

A solution of 2-bromo-5-(trifluoromethyl)pyridine (6.0 g, 26.55 mmol)and isopropyl amine (9.08 mL, 106.18 mmol) in sealed tube was maintainedat 100° C. for 8 h. The reaction mixture was diluted with water (50 mL)and extracted with ethyl acetate (2×150 mL). The combined organic layerwas washed with water (50 mL), brine (50 ml), dried over anhydrousNa₂SO₄ and concentrated. The crude product was purified by columnchromatography over silica gel (100-200 mesh) using a solvent gradientof 20% ethyl acetate in pet-ether to afford 5.0 g (92%) ofN-isopropyl-5-(trifluoromethyl)pyridin-2-amine 152-1 as an off whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (s, 1H), 7.58 (dd, J=2.8, 9.2Hz, 1H), 7.16 (d, J=6.8 Hz, 1H), 6.53 (d, J=8.8 Hz, 1H), 4.02-4.10 (m,1H), 1.14 (d, J=6.4 Hz, 6H). ESI-LC/MS: m/z 205.0 (M+H); R_(t)=4.57 min[Agilent LC with Ion trap Detector; Xterra MS-C18, 2.5 μm, 4.6×50 mmcolumn; gradient of 80:20 H₂O (0.01 M Ammonium Bicarbonate):CH₃CN to10:90 H₂O (0.01 M Ammonium Bicarbonate):CH₃CN in 4.0 minu and hold for3.0 min with flow rate of 1.0 mL/min].

Step 2

Compound 152-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield56%. Off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.62 (d,J=7.2 Hz, 1H), 8.13-8.17 (m, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.30 (s, 1H),6.76 (dd, J=1.6, 7.6 Hz, 1H), 4.87-4.94 (m, 1H), 1.31 (d, J=6.8 Hz, 6H).

Step 3

Compound 152 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 13%.Light yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.67-8.78(m, 3H), 8.59 (s, 1H), 8.16 (dd, J=2.5, 8.7 Hz, 1H), 8.11 (d, J=8.1 Hz,1H), 7.97-8.01 (m, 1H), 7.74 (s, 1H), 7.56 (d, J=8.5 Hz, 1H4), 6.80 (dd,J=1.9, 7.3 Hz, 1H), 4.88-4.97 (m, 1H), 2.86 (d, J=4.7 Hz, 3H), 1.32 (d,J=6.5 Hz, 6H). ESI-LC/MS: m/z 483.3 (M+H); R_(t)=3.92 min [Agilent LCwith Ion trap Detector; XBridge-C18, 3.5 μm, 4.6×75 mm column; gradientof 80:20 H₂O (0.005 M Ammonium Bicarbonate):CH₃CN to 10:90 H₂O (0.005 MAmmonium Bicarbonate):CH₃CN in 4.0 min and hold for 6.0 min with flowrate of 1.0 mL/min]. HPLC purity=98.9% at 230 nm; R_(t)=9.04 min [WatersHPLC with PDA; Symmetry Shield RP-18, 5.0 μm, 4.6×250 mm column;gradient of 90:10 H₂O (0.01% TFA):Methanol hold for 2.0 min and to 30:70H₂O (0.01% TFA):Methanol in 3.0 min and to 10:90 H₂O (0.01%TFA):Methanol in 3.0 min and hold for 10.0 min with flow rate of 1.0mL/min].

Example 153N-Isopropyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 153 was prepared using the general procedure described inSuzuki Procedure H with the appropriate starting materials. Yield 13%.Light yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.95 (s, 1H), 8.65 (d,J=6.6 Hz, 1H), 8.40-8.55 (m, 2H), 8.19 (d, J=8.1 Hz, 1H), 7.92 (d, J=8.5Hz, 2H), 7.65 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H),6.81 (dd, J=1.8, 7.0 Hz, 1H), 4.90-5.00 (m, 1H), 2.82 (d, J=4.4 Hz, 3H),1.32 (d, J=7.0 Hz, 6H). ESI-LC/MS: m/z 482.3 (M+H); R_(t)=3.84 min[Agilent LC with Ion trap Detector; XBridge-C18, 3.5 μm, 4.6×75 mmcolumn; gradient of 80:20 H₂O (0.005 M Ammonium Bicarbonate):CH₃CN to10:90 H₂O (0.005 M Ammonium Bicarbonate):CH₃CN in 4.0 min and hold for6.0 min with flow rate of 1.0 mL/min]. HPLC purity=>99% at 254 nm;R_(t)=8.95 min [Waters HPLC with PDA; Symmetry Shield RP-18, 5.0 μm,4.6×250 mm column; gradient of 90:10 H₂O (0.01% TFA):CH3CN hold for 2.0min and to 10:90 H₂O (0.01% TFA):CH3CN in 4.0 min and hold for 12.0minutes with flow rate of 1.0 mL/min].

Example 154N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

To a stirred solution of 6-bromo-N-methylpicolinamide (200 mg, 0.930mmol), hexamethylditin (0.191 mL, 0.933 mmol) in 1,2-dimethoxyethane(20.0 mL) was degassed with argon for about 15 min. Pd(PPh₃)₄ (107.8 mg,0.094 mmol) was added under argon atmosphere. The resulting reactionmixture was maintained at 80° C. for 16 h, allowed to room temperatureand was added to a mixture of3-bromo-N-(5-cyanopyridin-2-yl)-N-isopropylpyrazolo[1,5-a]pyridine-5-carboxamide148-2 (357 mg, 0.929 mmol) and Pd(PPh₃)₄ (107.8 mg, 0.094 mmol). Thereaction mixture was stirred at 90° C. for another 18 h. The reactionmixture was cooled to room temperature, extracted with ethyl acetate(100 mL). The organic layer was washed with water (2×100 mL), brine (50mL), dried over Na₂SO₄ and concentrated. The crude compound was purifiedby column chromatography over silica gel (100-200 mesh) using a solventgradient of 1-2% methanol in chloroform as an eluant followed byprep-TLC to afford 45 mg (11%) ofN-(5-cyanopyridin-2-yl)-N-isopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide154 as a yellow color solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.04 (d, J=2.0Hz, 1H), 8.97 (d, J=2.0 Hz, 1H), 8.78 (s, 1H), 8.66 (d, J=7.4 Hz, 1H),8.58-8.61 (m, 1H), 8.37 (s, 1H), 8.19-8.17 (m, 2H), 7.94 (d, J=8.3 Hz,1H), 7.50 (d, J=8.3 Hz, 1H), 6.83 (dd, J=2.4 Hz, 7.4 Hz, 1H), 4.91-4.98(m, 1H), 2.84 (d, J=4.4 Hz, 3H), 1.33 (d, J=6.8 Hz, 6H). ESI-LC/MS: m/z440.3 (M+H); R_(t)=3.25 min [Agilent LC with Ion trap Detector;XBridge-C18, 3.5 μm, 4.6×75 mm column; gradient of 80:20 H₂O (0.005 Mammonium bicarbonate):CH₃CN to 10:90 H₂O (0.005 M ammoniumbicarbonate):CH₃CN in 4.0 min and hold for 6.0 min with flow rate of 1.0mL/min]. HPLC purity: 95.5% at 292 nm; R_(t)=4.29 min [Waters HPLC withPDA; XBridge C-18, 5.0 μm, 4.6×150 mm column; gradient of 80:20 H₂O(0.01 M ammonium bicarbonate):CH₃CN to 10:90 H₂O (0.01 M ammoniumbicarbonate):CH₃CN in 6.0 min and hold for 6.0 min with flow rate of 1.0mL/min].

Example 155N-(5-Cyanopyridin-2-yl)-N-cyclobutyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

To a stirred solution of 6-bromo-N-methylpicolinamide (500 mg, 2.325mmol), hexamethylditin (0.483 mL, 2.331 mmol) in 1,2-dimethoxyethane(50.0 mL) was degassed with argon for about 15 min. Pd(PPh₃)₄ (270 mg,0.236 mmol) was added under argon atmosphere. The resulting reactionmixture was maintained at 80° C. for 16 h, allowed to room temperatureand added to a mixture of3-bromo-N-(5-cyanopyridin-2-yl)-N-cyclobutylpyrazolo[1,5-a]pyridine-5-carboxamide112-2 (922 mg, 2.328 mmol) and Pd(PPh₃)₄ (270 mg, 0.236 mmol). Thereaction mixture was stirred at 90° C. for 18 h. The reaction mass wascooled to room temperature, extracted with ethyl acetate (100 mL). Theorganic layer was washed with water, brine, dried over Na₂SO₄ andconcentrated. The crude compound was purified by column chromatographyover silica gel (100-200 mesh) using a solvent gradient of 1-2% methanolin chloroform as an eluant followed by prep-TLC to afford 60 mg (6%) ofN-(5-cyanopyridin-2-yl)-N-cyclobutyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide155 as a yellow color solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.04 (d, J=1.7Hz, 1H), 8.97 (d, J=1.8 Hz, 1H), 8.79 (s, 1H), 8.67 (d, J=7.3 Hz, 1H),8.58-8.60 (m, 1H), 8.39 (d, J=1.1 Hz, 1H), 8.29 (dd, J=2.6, 8.5 Hz, 1H),8.18 (dd, J=2.6, 8.5 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.4 Hz,1H), 6.86 (dd, J=2.2, 7.4 Hz, 1H), 4.85-5.00 (m, 1H), 2.84 (d, J=4.4 Hz,3H), 2.25-2.27 (m, 2H), 2.08-2.15 (m, 2H), 1.63-1.67 (m, 2H). ESI-LC/MS:m/z 452.3 (M+H); R_(t)=3.32 min [Agilent LC with Ion trap Detector;XBridge-C18, 3.5 μm, 4.6×75 mm column; gradient of 80:20 H₂O (0.005 Mammonium bicarbonate):CH₃CN to 10:90 H₂O (0.005 M ammoniumbicarbonate):CH₃CN in 4.0 min and hold for 3.0 min with flow rate of 1.0mL/min]. HPLC purity: 98.2% At 254 nm; R_(t)=1.78 min [Waters AcquityUPLC with PDA; Waters Acquity UPLC BEH C18, 1.7 μm, 2.1×100 mm column;gradient of 80:20 H₂O (0.025% TFA):CH₃CN (0.025% TFA) to 20:80 H₂O(0.025% TFA):CH₃CN (0.025% TFA) in 3.0 min and hold for 3.0 min withflow rate of 0.3 mL/min].

Example 156N-(5-fluoropyridin-2-yl)-N-isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 156 was prepared using the general procedure described inSuzuki Procedure G with the appropriate starting materials. Yield 2%.Yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 8.62 (d, J=1.4 Hz, 1H), 8.38(d, J=2.8 Hz, 1H), 8.26-8.31 (m, 2H), 8.17 (s, 1H), 8.00 (brs, 1H), 7.85(dd, J=2.4, 8.3 Hz, 1H), 7.73 (s, 1H), 7.29 (m, 1H), 6.94-6.99 (m, 1H),6.77 (dd, J=2.0, 7.3 Hz, 1H), 5.01-5.07 (m, 1H), 3.08 (d, J=4.9 Hz, 3H),1.31 (d, J=6.8 Hz, 6H). ESI-LC/MS: m/z 431.3 (M−H); R_(t)=3.41 min[Agilent LC with Ion trap Detector; XBridge-C18, 3.5 μm, 4.6×75 mmcolumn; gradient of 80:20 H₂O (0.005 M ammonium bicarbonate):CH₃CN to10:90 H₂O (0.01 M ammonium bicarbonate):CH₃CN in 4.0 min and hold for3.0 min with flow rate of 1.0 mL/min]. HPLC purity: 94.6% at 234 nm;R_(t)=5.29 min [Waters HPLC with PDA; XBridge-C18, 5.0 μm, 4.6×150 mmcolumn; gradient of 80:20 H₂O (0.01 M ammonium bicarbonate):CH₃CN to10:90 H₂O (0.01 M ammonium bicarbonate):CH₃CN in 6.0 min and hold for12.0 min with flow rate of 1.0 mL/min].

Example 157N-ethyl-3-(6-(methylcarbamoyl)pyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 157 was prepared using the general procedure described inSuzuki Procedure I with the appropriate starting materials. Yield 58%.yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.81-8.88 (m, 2H), 8.70-8.77(m, 2H), 8.65 (s, 1H), 8.18 (dd, J=2.26, 8.66 Hz, 1H), 8.03-8.11 (m,2H), 7.93-7.98 (m, 1H), 7.56 (d, J=8.53 Hz, 1H), 6.84 (dd, J=1.76, 7.28Hz, 1H), 4.13 (q, J=7.15 Hz, 2H), 2.86 (d, J=4.89 Hz, 3H), 1.22 (t,J=6.96 Hz, 3H). ESI-LC/MS: m/z 468.7 (M+H); R_(t)=0.97 min [AgilentUHPLC 1290 coupled with API 3200; Acquity UPLC BEH C18 column, 1.7 μm,2.1×50 mm; gradient of 98:2 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1%HCOOH):CH₃CN for 2 min run time with 1.0 mL/min flow rate]. HPLCpurity=98.7% at 254 nm; R_(t)=1.68 min [Waters Acquity UPLC equippedwith a Acquity UPLC HSS T3 column, 1.8 μm, 2.1×50 mm; gradient of 95:5H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1% HCOOH):CH₃CN for 2 min run timewith 1.0 mL/min flow rate].

Example 158N-(5-cyanopyridin-2-yl)-N-ethyl-3-(4-(methylsulfonyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 158 was prepared using the general procedure described inSuzuki Procedure I with the appropriate starting materials. Yield 53%.yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.88 (d, J=2.13 Hz, 1H), 8.71(d, J=7.15 Hz, 1H), 8.59 (s, 1H), 8.25 (dd, J=2.26, 8.53 Hz, 1H), 8.01(s, 2H), 7.99 (s, 1H), 7.82 (d, J=8.41 Hz, 2H), 7.55 (d, J=8.53 Hz, 1H),6.81 (dd, J=1.63, 7.28 Hz, 1H), 4.12 (q, J=6.99 Hz, 2H), 3.26 (s, 3H),1.21 (t, J=7.03 Hz, 3H). ESI-LC/MS: m/z 445.8 (M+H); R_(t)=0.89 min[Agilent UHPLC 1290 coupled with API 3200; Acquity UPLC BEH C18 column,1.7 μm, 2.1×50 mm; gradient of 98:2 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O(0.1% HCOOH):CH₃CN for 2 min run time with 1.0 mL/min flow rate]. HPLCpurity=98.1% at 254 nm; R_(t)=1.57 min [Waters Acquity UPLC equippedwith a Acquity UPLC HSS T3 column, 1.8 μm, 2.1×50 mm; gradient of 95:5H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1% HCOOH):CH₃CN for 2 min run timewith 1.0 mL/min flow rate].

Example 159N-ethyl-N-(5-fluoropyridin-2-yl)-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

To a stirred solution of3-bromo-N-ethyl-N-(5-fluoropyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide95-2 (500 mg, 1.377 mmol) in dioxane:water (3:1) (10.0 mL),N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(723.3 mg, 2.762 mmol), K₂CO₃ (419 mg, 3.036 mmol) were added anddegassed with argon for about 15 min. PdCl₂(dppf)CH₂Cl₂ complex (225.3mg, 0.275 mmol) was added under argon atmosphere. The resulting reactionmixture was maintained at 80° C. for 2 h, cooled to room temperature andfiltered through celite. The filtrate was partitioned between water (100mL) and ethyl acetate (100 mL). The ethyl acetate layer was washed withwater, brine, dried over anhydrous Na₂SO₄ and concentrated. The crudecompound was purified by column chromatography over silica gel (100-200mesh) using a solvent gradient of 60-70 ethyl acetate in pet-ether aseluant to afford 300 mg (52%) ofN-ethyl-N-(5-fluoropyridin-2-yl)-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide159 as a pale-yellow color solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.82 (s,1H), 8.67-8.74 (m, 2H), 8.62 (s, 1H), 8.46 (d, J=3.0 Hz, 1H), 8.09 (s,2H), 7.87 (s, 1H), 7.73 (td, J=3.3, 8.4 Hz, 1H), 7.42 (dd, J=3.6, 8.8Hz, 1H), 6.77 (dd, J=1.8, 7.3 Hz, 1H), 4.01 (q, J=7.0 Hz, 2H), 2.86 (d,J=4.8 Hz, 3H), 1.17 (t, J=7.0 Hz, 3H). ESI-LC/MS: m/z 417.3 (M−H);R_(t)=3.23 min [Agilent LC with Ion trap Detector; XBridge-C18, 3.5 μm,4.6×75 mm column; gradient of 80:20 H₂O (0.005 M ammoniumbicarbonate):CH₃CN to 20:80 H₂O (0.01 M ammonium bicarbonate):CH₃CN in4.0 min and hold for 3.0 min with flow rate of 1.0 mL/min]. HPLC purity:98.1% at 254 nm; R_(t)=1.92 min [Waters Acquity UPLC with PDA; WatersAcquity UPLC BEH C18, 1.7 μm, 2.1×100 mm column; gradient of 90:10 H₂O(0.025% TFA):CH₃CN (0.025% TFA) to 10:90 H₂O (0.025% TFA):CH₃CN (0.025%TFA) in 4.0 min and hold for 2.0 min with flow rate of 0.3 mL/min].

Example 160N-cyclobutyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

To a solution of 2-bromo-5-(trifluoromethyl)pyridine (10.0 g, 44.24mmol), K₂CO₃ (8.3 g, 60.05 mmol) in DMSO (50 mL) was addedcyclobutylamine (4.51 mL, 52.82 mmol) and maintained at 100° C. for 16 hin sealed tube. The reaction mixture was diluted with water andextracted with ethyl acetate (2×150 mL). The combined organic layerswere washed with water, brine solution, dried over anhydrous Na₂SO₄ andconcentrated. The crude product was purified by column chromatographyover silica gel (100-200 mesh) using a solvent gradient of 20% ethylacetate in pet-ether to afford 8.0 g (84%) ofN-cyclobutyl-5-(trifluoromethyl)pyridin-2-amine 160-1 as a white solid.¹H-NMR (400 MHz, DMSO-d₆): 8.26 (s, 1H), 7.55-7.63 (m, 2H), 6.50 (d,J=11.6 Hz, 1H), 4.30-4.33 (m, 1H), 2.23-2.31 (m, 2H), 1.82-1.93 (m, 2H),1.64-1.72 (m, 2H). ESI-LC/MS: m/z 217.06 (M+H); R_(t)=2.85 min [WatersAcquity UPLC with SQD; Waters Acquity UPLC BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 98:02 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) hold for0.8 min and to 45:55 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 2.0 min andhold for 1.0 min and to 0:100 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 0.5min and hold for 1.5 min with flow rate of 0.4 mL/min].

Step 2

Compound 160-2 was prepared using the general procedure described inAmide Coupling-Method 1 with the appropriate starting materials. Yield69%. yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.92-8.87 (m, 1H), 8.63(dd, J=13.08, 16.92 Hz, 1H), 8.24 (dd, J=2.36, 8.46 Hz, 1H), 7.61 (d,J=8.34 Hz, 1H), 7.36-7.32 (m, 1H), 6.78 (dd, J=1.77, 7.23 Hz, 1H),4.99-4.88 (m, 1H), 2.28-2.19 (m, 2H), 2.09 (pd, J=2.59, 9.80 Hz, 2H),1.74-1.55 (m, 2H).

Step 3

Compound 160 was prepared using the general procedure described inSuzuki Procedure I with the appropriate starting materials. Yield 72%.yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.95 (s, 1H), 8.66 (d, J=6.99Hz, 1H), 8.46 (s, 2H), 8.27 (d, J=9.21 Hz, 1H), 7.93 (d, J=7.58 Hz, 2H),7.71-7.62 (m, 2H), 7.50 (d, J=7.61 Hz, 2H), 6.83 (d, J=7.16 Hz, 1H),5.04-4.91 (m, 1H), 2.83 (s, 3H), 2.24 (d, J=7.62 Hz, 2H), 2.16-2.03 (m,3H), 1.75-1.56 (m, 2H). ESI-LC/MS: m/z 494 (M+H); R_(t)=1.01 min[Agilent UHPLC 1290 coupled with API 3200; Acquity UPLC BEH C18 column,1.7 μm, 2.1×50 mm; gradient of 98:2 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O(0.1% HCOOH):CH₃CN for 2 min run time with 1.0 mL/min flow rate]. HPLCpurity=99.7% at 254 nm; R_(t)=1.74 min [Waters Acquity UPLC equippedwith a Acquity UPLC HSS T3 column, 1.8 μm, 2.1×50 mm; gradient of 95:5H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1% HCOOH):CH₃CN for 2 min run timewith 1.0 mL/min flow rate].

Example 161 NN-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide

Compound 161 was prepared using the general procedure described inSuzuki Procedure I with the appropriate starting materials. Yield 42%.yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.94-8.92 (m, 1H), 8.81 (dd,J=0.86, 2.31 Hz, 1H), 8.76-8.69 (m, 2H), 8.62 (s, 1H), 8.27 (dd, J=2.52,8.52 Hz, 1H), 8.11 (dd, J=0.85, 8.18 Hz, 1H), 8.02 (dd, J=2.25, 8.17 Hz,1H), 7.77 (dd, J=0.97, 1.87 Hz, 1H), 7.64 (d, J=8.39 Hz, 1H), 6.86 (dd,J=1.81, 7.25 Hz, 1H), 5.03-4.90 (m, 1H), 2.87 (d, J=4.85 Hz, 3H),2.29-2.18 (m, 2H), 2.16-2.03 (m, 2H), 1.75-1.56 (m, 2H). ESI-LC/MS: m/z494.6 (M+H); R_(t)=1.01 min [Agilent UHPLC 1290 coupled with API 3200;Acquity UPLC BEH C18 column, 1.7 μm, 2.1×50 mm; gradient of 98:2 H₂O(0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1% HCOOH):CH₃CN for 2 min run timewith 1.0 mL/min flow rate]. HPLC purity=>99% at 254 nm; R_(t)=1.78 min[Waters Acquity UPLC equipped with a Acquity UPLC HSS T3 column, 1.8 μm,2.1×50 mm; gradient of 95:5 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1%HCOOH):CH₃CN for 2 min run time with 1.0 mL/min flow rate].

Example 162N-(5-cyano-6-(2-hydroxyethoxyl)pyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide

Step 1

To a solution of 2,6-dichloronicotinonitrile (500 mg, 2.89 mmol) inacetonitrile, 2M ethanamine in THF (3.61 mL, 7.23 mmol) were added to a20 mL microwave vial. The reaction mixture was stirred at roomtemperature for 16 h. The solvent was evaporated under vacuum. The crudecompound was purified by column chromatography over silica gel (100-200mesh) using a solvent gradient of 50% ethyl acetate in cyclohexane aseluant to afford 371 mg (71%) of yellow solid. The desired isomer wasconfirmed by 2D NOESY. ¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, J=8.64 Hz,1H), 6.27 (d, J=8.63 Hz, 1H), 5.14 (s, 1H), 3.37 (p, J=6.86 Hz, 2H),1.26 (t, J=7.23 Hz, 3H).

Step 2

Potassium tert-butoxide (458 mg, 4.08 mmol) was added to2-(benzyloxy)ethanol (0.726 ml, 5.10 mmol) in 15.0 mL of dioxane in amicrowave vial and stirred at room temperature for 15 min. Subsequently,2-chloro-6-(ethylamino)nicotinonitrile (370.7 mg, 2.041 mmol) in 15.0 mLof dioxane was added to the reaction mixture and it was stirred at 80°C. for 16 h. Reaction mixture was cooled to room temperature and dilutedwith water (50 mL) and extracted with ethyl acetate (2×50 mL). Theorganic layer was washed with water (50 mL), 1M hydrochloric acid (25mL), sat. sodium bicarbonate solution (25 mL), sat. NaCl (25 mL) anddried with anhydrous sodium sulfate. The crude compound was purified bycolumn chromatography over silica gel (100-200 mesh) using a solventgradient of 50% ethyl acetate in cyclohexane as eluant to afford 228 mg(75%) of 2-(2-(benzyloxy)ethoxy)-6-(ethylamino)nicotinonitrile 162-2.ESI-LC/MS: m/z 299.7 [(M+2)+H]; R_(t)=1.13 min. [Agilent UHPLC 1290coupled with API 3200; Acquity UPLC BEH C18 column, 1.7 μm, 2.1×50 mm;gradient of 98:2 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1% HCOOH):CH₃CNfor 2 min run time with 1.0 mL/min flow rate].

Step 3

Compound 162-3 was prepared using the general procedure described inamide coupling-Method 1 with the appropriate starting materials. Yield18%. ¹H NMR (400 MHz, CDCl₃): δ 8.25 (d, J=7.23 Hz, 1H), 7.94 (s, 1H),7.69 (d, J=8.08 Hz, 2H), 7.34 (d, J=4.49 Hz, 4H), 6.62-6.56 (m, 2H),4.56 (s, 2H), 4.35 (t, J=11.35, 12.39 Hz, 2H), 4.12 (q, J=7.05 Hz, 2H),3.71 (t, J=10.27, 12.81 Hz, 2H), 1.28 (t, J=7.06 Hz, 3H).

Step 4

Compound 162-4 was prepared using the general procedure described inSuzuki Procedure I with the appropriate starting materials. Yield 55%.yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.34 (d, J=7.39 Hz, 1H), 8.18(s, 1H), 7.88 (s, 1H), 7.83 (d, J=8.24 Hz, 2H), 7.70 (d, J=8.09 Hz, 1H),7.46 (d, J=8.24 Hz, 2H), 7.33 (d, J=4.34 Hz, 4H), 7.28 (d, J=3.78 Hz,3H), 6.70 (dd, J=1.65, 7.30 Hz, 1H), 6.57 (d, J=8.06 Hz, 1H), 6.24 (d,J=4.78 Hz, 1H), 4.58 (s, 2H), 4.39 (t, J=5.44, 8.70 Hz, 2H), 4.12 (q,J=7.04 Hz, 2H), 3.74 (dt, J=4.71, 9.43 Hz, 2H), 3.01 (d, J=4.79 Hz, 3H),1.28 (t, J=7.05 Hz, 3H). ESI-LC/MS: m/z 575 (M+H); R_(t)=1.08 min.[Agilent UHPLC 1290 coupled with API 3200; Acquity UPLC BEH C18 column,1.7 μm, 2.1×50 mm; gradient of 98:2 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O(0.1% HCOOH):CH₃CN for 2 min run time with 1.0 mL/min flow rate].

Step 5

N-(6-(2-(benzyloxy)ethoxy)-5-cyanopyridin-2-yl)-N-ethyl-3-(4(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide 162-4 (95mg, 0.165 mmol) and palladium on carbon (1.759 mg, 0.017 mmol) wereadded to ethanol in a 8 ml vial. Hydrogen gas was bubbled into thereaction mixture for 16 h under constant stirring. Reaction mixturefiltered through celite bed and the filterate was evaporated to getyellow residue. And the residue was purified by auto-prep (solventsystem: 35-95% ACN in 8 mins, LOW pH SUNFIRE). The fractions wereconcentrated and lypholised to give 9.6 mg (12%) ofN-(5-cyano-6-(2-hydroxyethoxyl)pyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide162 as fluorescent yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.68 (d,J=7.18 Hz, 1H), 8.52 (s, 1H), 8.47 (d, J=4.57 Hz, 1H), 8.16 (d, J=8.17Hz, 1H), 8.01 (s, 1H), 7.93 (d, J=8.36 Hz, 2H), 7.65 (d, J=8.35 Hz, 2H),7.05 (d, J=8.18 Hz, 1H), 6.78 (dd, J=1.70, 7.22 Hz, 1H), 4.86 (t, J=5.35Hz, 1H), 4.15 (t, J=9.98, 11.12 Hz, 2H), 4.08 (q, J=6.82 Hz, 2H), 3.53(q, J=5.18 Hz, 2H), 2.82 (d, J=4.48 Hz, 3H), 1.23 (t, J=6.99 Hz, 3H).ESI-LC/MS: m/z 485.8 (M+H); R_(t)=0.81 min. [Agilent UHPLC 1290 coupledwith API 3200; Acquity UPLC BEH C18 column, 1.7 μm, 2.1×50 mm; gradientof 98:2 H₂O (0.1% HCOOH):CH₃CN to 2:98 H₂O (0.1% HCOOH):CH₃CN for 2 minrun time with 1.0 mL/min flow rate]. HPLC purity=98% at 254 nm;R_(t)=1.44 min [Waters Acquity UPLC equipped with a Acquity UPLC HSS T3column, 1.8 μm, 2.1×50 mm; gradient of 95:5 H₂O (0.1% HCOOH):CH₃CN to2:98 H₂O (0.1% HCOOH):CH₃CN for 2 min run time with 1.0 mL/min flowrate].

Example 1634-(5-(N-(5-Cyanopyridin-2-yl)-N-methylsulfamoyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide

Step 1

A solution mixture of tert-butyl pyridin-4-ylcarbamate (23.0 g, 118.55mmol) was treated with O-(mesitylsulfonyl)hydroxylamine (25.49 g, 118.55mmol) in acetonitrile (180 mL) at room temperature for overnight in asealed tube and then solvent was evaporated under reduced pressure. Theresulting crude compound was dissolved in DMF (250 mL), added to amixture of K₂CO₃ (40.9 g, 296.37 mmol) and ethyl propiolate (11.99 mL,118.55 mmol). The resulting reaction mixture was stirred at roomtemperature for 16 h. The reaction mixture was quenched with ice-coldwater, the precipitated solid was collected by filtration and dried. Thecrude compound was purified by column chromatography over silica gel(100-200 mesh) using a solvent gradient of 20-30% ethyl acetate inpet-ether as eluant to afford 10.5 g (29%) of ethyl5-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate163-1 as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆): 10.01 (s, 1H),8.70 (d, J=7.2 Hz, 1H), 8.35 (d, J=2.1, 1H), 8.29 (s, 1H), 7.12 (dd,J=2.4, 7.5 Hz, 2H), 4.26 (q, J=6.9 Hz, 2H), 1.51 (s, 9H), 1.32 (t, J=6.9Hz, 3H).

Step 2

Ethyl5-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate163-1 (10.0 g, 32.751 mmol) was treated with 40% H₂SO₄ (80 mL) at refluxtemperature for 4 h. The reaction mixture was taken up in water (100mL), pH was adjusted to 8.0 with aq. 20% NaOH solution. The aq. layerwas extract with ethyl acetate (3×100 mL). The combined extracts werewashed with brine (2×50 mL), dried over anhyd. Na₂SO₄ and concentratedto afford 2.5 g (57%) of pyrazolo[1,5-a]pyridin-5-amine 162-2 as an palebrown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.25 (d, J=5.4 Hz, 1H), 7.65(d, J=1.5 Hz, 1H), 6.40 (d, J=1.8 Hz, 1H), 6.31 (dd, J=1.8, 5.4 Hz, 1H),5.98 (d, J=1.2 Hz, 1H), 5.56 (s, 2H). ESI-LC/MS: m/z 133.9 (M+H);R_(t)=1.53 min. [Agilent LC with Ion trap Detector; XBridge-C18, 3.5 μm,4.6×75 mm column; gradient of 80:20 H₂O (0.005 M Ammonium Bicarbonate):CH₃CN to 10:90 H₂O (0.01 M Ammonium Bicarbonate):CH₃CN in 4.0 minutesand hold for 3.0 min with flow rate of 1.0 mL/min].

Step 3

A solution of NaNO₂ (114 mg, 1.652 mmol) dissolved in water (0.3 mL) wasadded drop-wise to a suspension of pyrazolo[1,5-a]pyridin-5-amine 163-2(200 mg, 1.503 mmol) in con. HCl:CH₃COOH (3:1) (1.0 mL) at −10° C. andthe reaction mixture was maintained between −15° C. to −5° C. for 45min. CuCl (37 mg, 0.373 mmol) was added to the solution of SO₂ gas inacetic acid (1.0 mL) (prepared by purging SO₂ gas in aceticacid for 20min) and purged SO₂ gas further 10 more minutes. To this resultingsolution was added above prepared solution (diazonium salt of 163-2) asdrop-wise at 0° C. and the resulting reaction mixture was stirred for 5min. The reaction mixture was poured on to ice cold water (25 mL),extracted the product into ethyl acetate (2×20 mL), and the organiclayer was washed with water, brine solution, dried over anhyd. Na₂SO₄,concentrated under reduced pressure to afford 130 mg (crude) ofpyrazolo[1,5-a]pyridine-5-sulfonyl chloride 163-3 as a brown gummy mass.ESI-LC/MS: m/z 217.02 (M+H) & 218.97 [(M+2)+H]; R_(t)=1.88 min [WatersAcquity UPLC with Quattro-micro detector; Waters Acquity BEH C18, 1.7μm, 2.1×50 mm column; gradient of 90:10 H₂O (0.1% HCOOH):CH₃CN (0.1%HCOOH) hold for 0.6 min and to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH)in 2.0 min and hold for 3.0 min with flow rate of 0.4 mL/min].

Step 4

To a suspension of NaH (60%) (16.5 mg, 0.413 mmol) in THF (2.0 mL) at 0°C. was added 6-(methylamino)nicotinonitrile (50 mg, 0.375 mmol) andstirred for 5 min and then was added a solution ofpyrazolo[1,5-a]pyridine-5-sulfonyl chloride 163-3 (97 mg, 0.447 mmol) inTHF (1.0 mL). The resulting reaction mixture was stirred at rt for 2 h.Quenched the reaction mixture by adding brine solution (10 mL),extracted the product into ethyl acetate 2×25 mL). The combined extractswere washed with water (20 mL), brine solution (20 ML), dried overanhyd. Na₂SO₄, concentrated under reduced pressure. This crude compoundon purification by pre-TLC gave 15 mg (13% over two steps) ofN-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-sulfonamide164-4 as a off-white solid. ESI-LC/MS: m/z 314.06 (M+H); R_(t)=1.85 min.[Waters HPLC with SQD; Waters X-Bridge BEH C18, 2.5 μm, 3.0×50 mmcolumn; gradient of 90:10 H₂O (0.05% TFA):CH₃CN (0.05% TFA) hold for 0.6min and to 10:90 H₂O (0.05% TFA):CH₃CN (0.05% TFA) in 2.0 min and holdfor 3.0 min with flow rate of 0.7 mL/min].

Step 5

NBS (28.4 mg, 0.159 mmol) was added to a solution ofpyrazolo[1,5-a]pyridine-5-sulfonyl chloride 163-4 (50 mg, 0.159 mmol) inDMF (1.0 mL) at rt and stirred for 30 min. The reaction mixture wasdiluted with water and extracted the product into ethyl acetate (2×20mL). The organic layer was washed with water, brine, dried overanhydrous Na₂SO₄, and concentrated. The crude compound was purified bypreparative-TLC to afford 45 mg (72%) of3-bromo-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-sulfonamide163-5 as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.58 (d, J=2.0Hz, 1H), 8.43 (d, J=7.6 Hz, 1H), 8.04-8.07 (m, 2H), 7.95 (dd, J=2.0, 8.8Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 6.82 (dd, J=2.0, 7.2 Hz, 1H), 3.45 (s,3H). ESI-LC/MS: m/z 392 (M+H) & 394 [(M+2)+H]; R_(t)=2.59 min. [AgilentRRLC; Waters Acquity CSH C18, 1.7 μm, 2.1×50 mm column; gradient of98:02 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) hold for 0.5 min and to 55:45H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 1.2 min and to 25:75 H₂O (0.1%HCOOH):CH₃CN (0.1% HCOOH) in 2.5 min and to 0:100 H₂O (0.1% HCOOH):CH₃CN(0.1% HCOOH) in 3.2 min hold for 1.8 min with flow rate of 0.4 mL/min].

Step 6

Compound 163 was prepared using the general procedure described inSuzuki Procedure I with the appropriate starting materials. Yield 49%.yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.90 (d, J=7.6 Hz, 1H), 8.81(d, J=2.4 Hz, 1H), 8.66 (s, 1H), 8.44-8.50 (m, 1H), 8.32-8.36 (m, 2H),7.98 (d, J=7.6 Hz, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.8 Hz, 1H),7.08 (dd, J=2.0, 7.6 Hz, 1H), 3.45 (s, 3H), 2.82 (d, J=4.4 Hz, 3H).ESI-LC/MS: m/z 447.18 (M+H); R_(t)=1.81 min. [Waters Acquity UPLC withQuattro-micro detector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mmcolumn; gradient of 90:10 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) hold for0.6 min and to 10:90 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 2.0 min andhold for 3.0 min with flow rate of 0.4 mL/min]. HPLC purity=>99% at 254nm; R_(t)=3.83 min [Waters HPLC with PDA; XBridge C-18, 3.5 μm, 4.6×75mm column; gradient of 90:10 H₂O (0.01 M Ammonium acetate):CH₃CN to05:95 H₂O (0.01 M Ammonium acetate):CH₃CN in 4.0 min and hold for 8.0min with flow rate of 1.0 mL/min].

Example 1644-(5-(N-(5-Cyanopyridin-2-yl)-N-cyclopropylsulfamoyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide

Step 1

To a suspension of NaH (60%) (384 mg, 9.615 mmol) in THF (5.0 mL) wasadded a solution of 6-(cyclopropylamino)nicotinonitrile (913 mg, 5.73mmol) at 0° C. and stirred for 10 min. To this reaction mixture wasadded a solution of pyrazolo[1,5-a]pyridine-5-sulfonyl chloride 163-3(630 mg, 2.86 mmol) in THF (20.0 mL) and the resulting reaction mixturewas stirred at rt for 2 h. The reaction mixture was quenched by addingbrine solution (25 mL), extracted the product in to ethyl acetate (2×25mL). The combined extracts were washed with 2 N HCl (25 mL), water (25mL), brine (25 mL), dried over anhydrous Na₂SO₄, and the solvent wasdistilled off under reduced pressure. The crude compound was passedthrough a column of silica gel (100-200 mesh) using a solvent gradientof 30% ethyl acetate in pet-ether as eluant and obtained 200 mg (crude)ofN-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-sulfonamide164-1 as a brown color gummy solid. The crude product was used as suchin step without further purification.

Step 2

NBS (105 mg, 0.589 mmol) was added to a solutionN-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-sulfonamide164-1 (200 mg, 0.589 mmol) in DMF (2.0 mL) at rt and stirred for 30 min.The reaction mixture was diluted with water and extracted the productinto ethyl acetate (50 mL). The organic layer was washed with water (25mL), brine (25 mL), dried over anhydrous Na₂SO₄, and concentrated toafford 300 mg (17% over three steps) of3-bromo-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-sulfonamide164-2 as an off-white solid. ESI-LC/MS: m/z 418.09 (M+H) & 420.09[(M+2)+H]; R_(t)=2.14 min. [Waters Acquity UPLC with Quattro-microdetector; Waters Acquity BEH C18, 1.7 μm, 2.1×50 mm column; gradient of90:10 H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) hold for 0.6 min and to 10:90H₂O (0.1% HCOOH):CH₃CN (0.1% HCOOH) in 2.0 min and hold for 3.0 min withflow rate of 0.4 mL/min].

Step 3

Compound 164 was prepared using the general procedure described inSuzuki Procedure I with the appropriate starting materials. Yield 21%.yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (d, J=7.6 Hz, 1H), 8.87(s, 1H), 8.67 (s, 1H), 8.44-8.50 (m, 1H), 8.40 (dd, J=2.4, 8.8 Hz, 1H),8.32 (s, 1H), 7.98 (d, J=7.6 Hz, 2H), 7.74 (d, J=8.0, 2H), 7.64 (d,J=8.8 Hz, 1H), 7.13 (dd, J=1.6, 7.6 Hz, 1H), 3.00-3.06 (m, 1H), 2.82 (d,J=4.4 Hz, 3H), 0.935-0.949 (m, 2H), 0.68-0.699 (m, 2H). ESI-LC/MS: m/z473.0 (M+H); R_(t)=6.10 min [Agilent LC with Ion trap Detector;XBridge-C18, 3.5 μm, 4.6×75 mm column; gradient of 95:05 H₂O (0.005 MAmmonium Bicarbonate):CH₃CN hold for 1.0 min and to 85:15 H₂O (0.005 MAmmonium Bicarbonate):CH₃CN in 2.0 min and to 45:55 H₂O (0.005 MAmmonium Bicarbonate):CH₃CN in 4.5 min and to 0:100 H₂O (0.005 MAmmonium Bicarbonate):CH₃CN in 6.0 min hold for 3.0 min with flow rateof 1.0 mL/min]. HPLC purity=>99% at 254 nm; R_(t)=4.30 min [Waters HPLCwith PDA; XBridge C-18, 3.5 μm, 4.6×100 mm column; gradient of 90:10 H₂O(0.01 M Ammonium acetate):CH₃CN to 05:95 H₂O (0.01 M Ammoniumacetate):CH₃CN in 4.0 min and hold for 11.0 min with flow rate of 1.0mL/min].

Example 1654-(5-(N-(5-cyanopyridin-2-yl)-N-cyclopropylsulfamoyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide

Compound 165 was prepared using the general procedure described inSuzuki Procedure I with the appropriate starting materials. Yield 46%.yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (d, J=7.2 Hz, 1H), 8.87(d, J=2.0 Hz, 1H), 8.67 (s, 1H), 8.40 (dd, J=2.0, 8.4 Hz, 1H), 8.32 (s,1H), 7.98-8.06 (m, 3H), 7.74 (d, J=8.4, 2H), 7.64 (d, J=8.4 Hz, 1H),7.38 (br s, 1H), 7.13 (dd, J=1.6, 8.0 Hz, 1H), 3.00-3.08 (m, 1H),0.92-0.98 (m, 2H), 0.65-0.72 (m, 2H). ESI-LC/MS: m/z 459.21 (M+H);R_(t)=1.54 min [Waters Acquity UPLC with SQD; Waters Acquity UPLC BEHC18, 1.7 μm, 2.1×50 mm column; gradient of 97:03 H₂O (0.05% TFA):CH₃CN(0.05% TFA) hold for 0.2 min and to 65:35 H₂O (0.05% TFA):CH₃CN (0.05%TFA) in 1.0 min and to 02:98 H₂O (0.05% TFA):CH₃CN (0.05% TFA) in 2.0min and hold for 1.85 min with flow rate of 0.6 mL/min]. HPLCpurity=>99% at 254 nm; R_(t)=4.14 min [Waters HPLC with PDA; XBridgeC-18, 3.5 μm, 4.6×100 mm column; gradient of 90:10 H₂O (0.01 M Ammoniumacetate):CH₃CN to 05:95 H₂O (0.01 M Ammonium acetate):CH₃CN in 4.0 minand hold for 11.0 min with flow rate of 1.0 mL/min].

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

We claim:
 1. A compound of Formula I,

or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof,wherein n is 0, 1, 2 or 3; p is 0, 1, 2 or 3; L is selected from thegroup consisting of *—(CHR₃)₁₋₃—, *—CHR₃N(R₂)—, *—CHR₃O—, *—CHR₃S—,*—CHR₃S(O)—, *—CHR₃N(R₂)CHR₃—, *—C(O)—, *—C(O)N(R₂)—, *—C(O)N(R₂)CHR₃—,*—N(R₂)—, *—N(R₂)CHR₃—, *—N(R₂)C(O)—, *—N(R₂)C(O)N(R₂)—, *—N(R₂)S(O)₂—,wherein * represents the point of attachment of L to thepyrazolo[1,5-a]pyridine fused ring depicted in Formula I; each R₂ isindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,haloC₁₋₆alkyl, R—C₀₋₄alkylene, and R—C₀₋₄alkylene-C(O)—, wherein R isselected from the group consisting of hydroxyl, C₁₋₄alkoxy, amino,C₁₋₄alkylamino, C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, andC₅₋₆heteroaryl, wherein the C₃₋₆cycloalkyl, C₄₋₆heterocycloalkyl, andC₅₋₆heteroaryl of R are each unsubstituted or substituted with 1-2substituents independently selected from the group consisting of halo,amino, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxy, oxo, and C₅₋₆heteroaryl; andeach R₃ is independently selected from the group consisting of hydrogenand C₁₋₄alkyl; Ring A is selected from the group consisting of C₆₋₁₀aryland C₅₋₁₀heteroaryl; Ring C is selected from the group consisting ofC₆₋₁₀aryl, C₆₋₁₀heteroaryl, C₅₋₇cycloalkyl, C₅₋₇heterocycloalkyl, andfused bicyclyl comprising a C₅₋₆heterocycloalky fused to a phenyl; eachR₁ is independently selected from the group consisting of halo, cyano,amino, C₁₋₄alkyl, C₁₋₄alkoxyl, halo-C₁₋₄alkyl, —C(O)NR₇R₈, —NHC(O)R₁₁,phenyl, and C₅₋₆heteroaryl; wherein the phenyl and C₅₋₆heteroaryl of R₁are each unsubstituted or substituted with 1-2 substituentsindependently selected from the group consisting of C₁₋₄alkyl, amino,halo, and C₁₋₄alkylamino; R₇ and R₈ are each independently selected fromhydrogen, C₁₋₄alkyl and haloC₁₋₄alkyl; R₁₁ is C₁₋₆alkyl, unsubstitutedor substituted with 1-2 substituents independently selected from thegroup consisting of amino, C₃₋₆cycloalkyl and C₄₋₆heterocycloalkyl; R₁₇is selected from the group consisting of cyano, halo, C₁₋₄alkyl,halo-C₁₋₄alkyl, oxo, C₃₋₆cycloalkyl, and —SO₂—C₁₋₄alkyl.
 2. The compoundof claim 1, wherein L is selected from the group consisting of*—C(O)N(R₂)— and *—N(R₂)C(O)—, wherein each R₂ is independently selectedfrom hydrogen, C₁₋₄alkyl, and R—C₀₋₄alkylene, and wherein R is selectedfrom the group consisting of C₁₋₄alkylamino, C₃₋₆cycloalkyl,C₄₋₆heterocycloalkyl and C₅₋₆heteroaryl, each of which is unsubstitutedor substituted with 1-2 substituents independently selected from thegroup consisting of halo, amino, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxy, oxo,and C₅₋₆heteroaryl.
 3. The compound of claim 1, wherein L is selectedfrom *—C(O)N(CH₃)—*—C(O)N(CH₂CH₃)—, *—C(O)N(CH(CH₃)₂)—,*—C(O)N(NH(CH₃))—, and *—N(CH₃)C(O)—.
 4. The compound according to claim1, wherein Ring A is selected from the group consisting of phenyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolopyridinyl, andindazolyl, each of which is unsubstituted or substituted by (R₁)_(n). 5.The compound according to claim 1, wherein Ring C is selected from thegroup consisting of

each of which is unsubstituted or substituted by (R₁₇)_(p).
 6. Thecompound according to claim 1, wherein Ring C is selected from the groupconsisting of phenyl and pyridinyl, each of which is unsubstituted orsubstituted by (R₁₇)_(p).
 7. The compound according to claim 1, whereineach R₁ is independently selected from the group consisting oftrifluoromethyl, cyano, —NH₂—, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, and—NHC(O)CH(NH₂)(CH₃).
 8. The compound according to claim 1, wherein eachR₁₇ is independently selected from the group consisting of cyano, halo,C₁₋₄alkyl, haloC₁₋₄alkyl, —SO₂—C₁₋₄alkyl, and C₃₋₆cycloalkyl.
 9. Thecompound of claim 1, wherein the compound is of Formula Ia:

or a pharmaceutical acceptable salt, tautomer or stereoisomer thereof,wherein n is 1 or 2; n is 1 or 2; Ring A is phenyl, pyridinyl, orpyrimidinyl; Ring C is phenyl or pyridinyl; L is *—C(O)NR₂— or*—NR₂C(O)—, wherein R₂ is selected from hydrogen, C₁₋₄alkyl,C₁₋₄alkylamino-(C₀₋₄)alkylene, C₃₋₆cycloalkyl-(C₀₋₄)alkylene,C₄₋₆heterocycloalkyl-(C₀₋₄)alkylene, wherein the C₄₋₆heterocycloalkyl isselected from the group consisting of piperazinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, and oxetanyl, and wherein theC₃₋₆cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl; each R₁ is independently *—C(O)NR₇R₈ or —NH₂—, wherein R₇and R₈ are each independently hydrogen or C₁₋₄alkyl; and R₁₇ is selectedfrom the group consisting of cyano, halo, —NH₂—, —C(O)NH₂, —C(O)NH(CH₃),and —C(O)N(CH₃)₂.
 10. The compound of claim 9, wherein L is selectedfrom *—C(O)N(CH₃)—*—C(O)N(CH₂CH₃)—, *—C(O)N(CH(CH₃)₂)—,*—C(O)N(NH(CH₃))—, and *—N(CH₃)C(O)—.
 11. The compound of claim 1,wherein the compound, or a pharmaceutical acceptable salt, tautomer orstereoisomer thereof, is selected from the group consisting of:N-(4-cyanophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-fluoro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)aniline;N-(4-chlorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-fluorophenyl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-N-(5-methylpyridin-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-chloro-N-methyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)aniline;N,5-dimethyl-N-((3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)methyl)yridine-2-amine;5-((4-fluorophenoxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;N-(4-cyanophenyl)-N-(2-methoxyethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-(2-(dimethylamino)ethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-(methylsulfonyl)phenyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-N-(5-methylpyridin-3-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-(((5-methylpyridin-2-yl)oxy)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;5-(4-fluorophenethyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;N-(4-cyanophenyl)-N-methyl-3-(1-methyl-1H-indazol-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-acetamidopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;5-(((4-fluorophenyl)thio)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;5-(((4-fluorophenyl)sulfinyl)methyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine;3-(4-(1H-pyrazol-5-yl)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-(trifluoromethyl)pyridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;(S)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)benzamide;4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)benzamide;4-cyano-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide;4-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-yl)benzenesulfonamide;3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-3-(4-(trifluoromethyl)phenyl)-N-(5-(trifluoromethyl)yridine-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-methyl-N-(5-(methylsulfonyl)pyridine-2-yl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-amineN-(4-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-amine;N-methyl-6-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)nicotinamide;N-methyl-5-(trifluoromethyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]yridine-5-yl)picolinamide;4-cyano-N-((tetrahydro-2H-pyran-4-yl)methyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-aminophenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-(2-aminoacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(S)-3-(4-(2-amino-3-methylbutanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(S)-3-(4-(2-amino-2-cyclohexylacetamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-fluorophenyl)-1-methyl-1-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)urea;6-(1,1-difluoroethyl)-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide;6-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)nicotinamide;4-cyclopropyl-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;5-fluoro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide;N-methyl-4-(methylsulfonyl)-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-aminopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-chloro-N-methyl-N-(3-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-(3-(4-carbamoylphenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-fluoro-N-methylbenzamide4-fluoro-N-methyl-N-(3-(4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)benzamide;N-methyl-N-(5-(methylsulfonyl)pyridin-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-3-(5-methoxypyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-methyl-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-methyl-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-fluorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;4-(5-(1-(7-fluoro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;N-(4-cyanophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-(5-(1-(methyl(5-methylpyridin-2-yl)amino)ethyl)pyrazolo[1,5-a]pyridin-3-yl)phenyl)acetamide;3-(4-acetamidophenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide;4-(5-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;4-(5-(7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(1-(1H-pyrazol-1-yl)propan-2-yl)-3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-fluoropyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-amino-3,5-dimethylphenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-methylpyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-cyanocyclohexyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-cyanopyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-amino-5-methoxypyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-chloro-2-formylphenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-(5-(1-(4-cyanophenyl)-2-methylhydrazinecarbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylpicolinamide;N-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;andN-ethyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide.12. The compound of claim 1, wherein the compound, a pharmaceuticalacceptable salt, tautomer, or stereoisomer thereof, is selected from thegroup consisting of:3-(4-carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-cyanophenyl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-aminopyridin-3-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;(R)-3-(4-(2-aminopropanamido)phenyl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(2-aminopyrimidin-5-yl)-N-(4-cyanophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;and3-(6-amino-5-(dimethylcarbamoyl)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide.13. The compound of claim 1, wherein the compound, a pharmaceuticalacceptable salt, tautomer, or stereoisomer thereof, is selected from thegroup consisting of:N-(5-Cyanopyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-(5-(1-(4-cyanophenyl)-2-methylhydrazinecarbonyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylpicolinamide;N-(5-cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-methyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide3-(5-Amino-6-chloropyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Chlorophenyl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-Carbamoylphenyl)-N-(4-chlorophenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-((5-Cyanopyridin-2-yl)(methyl)carbamoyl)pyrazolo[1,5-a]pyridin-3-yl)benzoicacid;N-(5-Cyanopyridin-2-yl)-3-(4-((2-hydroxyethyl)carbamoyl)phenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-Methyl-3-(4-(methylcarbamoyl)phenyl)-N-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-((2-Aminoethyl)carbamoyl)phenyl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-Carbamoylphenyl)-N-(4-cyanophenyl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-Chloro-5-(methylsulfonamido)pyridin-3-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(2-Aminopyridin-4-yl)-N-(5-cyanopyridin-2-yl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Chlorophenyl)-N-methyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-(2-hydroxyethyl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-(2-Aminoethoxy)pyridin-2-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclobutyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-methyl-3-(4-(piperidin-4-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-methyl-3-(4-((2-(methylamino)ethyl)carbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-3-(4-((2-(dimethylamino)ethyl)carbamoyl)phenyl)-N-methylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Chlorophenyl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-(cyclopropylmethyl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(tert-Butyl)-N-(5-cyanopyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-Carbamoylphenyl)-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(isopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(6-Methoxypyridin-3-yl)-N-methyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(cyclopropylcarbamoyl)phenyl)pyrazolo[1,5a]pyridine-5-carboxamide;N-(5-Chloropyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Cyclopropyl-N-(5-fluoropyridin-2-yl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5a] pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopentyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(ethylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;6-(N-Cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamido)nicotinic acid;N-(5-Carbamoylpyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Cyclopropyl-N-(3,4-difluorophenyl)-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(4-(oxetan-3-ylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Cyclopropyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-carbamoylphenyl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(4-Carbamoylphenyl)-N-cyclopropyl-N-(3,4-difluorophenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Cyclopropyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-methylpyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-cyclopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(6-Carbamoylpyridin-3-yl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-Carbamoylpyridin-2-yl)-N-(5-cyanopyridin-2-yl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-ethyl-3-(4-[N-methylsulfamoyl]phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-cyclopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;3-(5-Carbamoylpyridin-2-yl)-N-(4-cyanophenyl)-N-cyclopropylpyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Chlorophenyl)-N-cyclopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(4-Cyanophenyl)-N-isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;5-Cyano-N-cyclopropyl-N-(3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridin-5-yl)picolinamide;N-(5-Cyanopyridin-2-yl)-N-isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyano-6-methoxypyridin-2-yl)-N-cyclopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-ethyl-3-(6-[methylcarbamoyl]pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-fluoropyridin-2-yl)-N-isopropyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-Isopropyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-isopropyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-Cyanopyridin-2-yl)-N-cyclobutyl-3-(5-(methylcarbamoyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-fluoropyridin-2-yl)-N-isopropyl-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-3-(6-(methylcarbamoyl)pyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyanopyridin-2-yl)-N-ethyl-3-(4-(methylsulfonyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-ethyl-N-(5-fluoropyridin-2-yl)-3-(6-(methylcarbamoyl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-cyclobutyl-3-(4-(methylcarbamoyl)phenyl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;NN-cyclobutyl-3-(6-(methylcarbamoyl)pyridin-3-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazolo[1,5-a]pyridine-5-carboxamide;N-(5-cyano-6-(2-hydroxyethoxy)pyridin-2-yl)-N-ethyl-3-(4-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-5-carboxamide;4-(5-(N-(5-Cyanopyridin-2-yl)-N-methylsulfamoyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;4-(5-(N-(5-Cyanopyridin-2-yl)-N-cyclopropylsulfamoyl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide;and4-(5-(N-(5-cyanopyridin-2-yl)-N-cyclopropylsulfamoyl)pyrazolo[1,5-a]pyridin-3-yl)benzamide.14. A pharmaceutical composition comprising at least one compound ofclaim 1 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, diluent or excipient.
 15. A methodfor treating or preventing malaria, comprising administering to asubject a therapeutically effective amount of a compound according toclaim 1, wherein the administering may be in combination with a secondagent.
 16. A method for treating or preventing malaria, comprisingadministering to a subject a therapeutically effective amount of apharmaceutical composition according to claim 14, wherein theadministering may be in combination with a second agent.
 17. The methodaccording to claim 16, wherein the second agent is an antimalarial drugselected from artemisinin, artemether, artesunate, arteflene,dihydroartemisinin, chlorproguanil, trimethoprim, chloroquine, quinine,mefloquine, amodiaquine, atovaquone, proguanil, lumefantrine,piperaquine, pyronaridine, halofantrine, pyrimethamine-sulfadoxine,quinacrine, pyrimethamine-dapsone, quinidine, amopyroquine,sulphonamides, primaquine, ferroquine, tafenoquine, arterolane, andpyronaridine.